HUT64541A - A new method and intermediate compounds for producing carbocephemes - Google Patents

Description

EXTRACT

A novel process and compounds for the preparation of carbacephems

LIVE LILLY AND COMPANY, INDIANAPOLIS, Indiana,

USA

Date of filing: 12/02/1993

Priority: February 18, 1992 (07 / 837,173),

USA

The present invention relates to novel compounds for the preparation of carbacephems.

A further object of the present invention is to provide simple, effective and high yielding processes for the preparation of chiral carbacephem compounds.

It is a further object of the present invention to provide a synthesis method for the preparation of carbacephems which eliminates the need for chemical or enzymatic degradation.

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New process and compounds. for the preparation of carbacephems

LIVE LILLY AND COMPANY, INDIANAPOLIS, Indiana, UNITED STATES OF AMERICA

inventors .:

FISHER Jack Wayne, INDIANAPOLIS,

HATFIELD Lowell Deloss, ZIONSVILLE,

HOYING Richard Charles, PLAINFIELD,

RAY James Edward, INDIANAPOLIS, \ l.t \ í ».H <“ - UNITED STATES OF AMERICA

Date of filing: 12/02/1993

Priority: February 18, 1992 (07 / 837,173),

USA

The present invention relates to a process for the preparation of 1-carbacephems such as 1-carba (1-dethia) -3-cephem-4-carboxylic acids, and to compounds and methods for this. The present invention provides novel methods that are easy to implement and provide high product yields. It also provides novel compounds for a variety of purposes, including as intermediates in the processes of the invention.

1-Carba (1-detia) -3-cephem-4-carboxylic acids, hereinafter referred to as 1-carbacephalosporins or cephalosporin analogs, are known as useful antibiotics. Because of the importance of these new β-lactam antibiotics, we need to find new, improved methods for their production.

For the preparation of 1-carbacephalosporins and their C-3 substituted methyl derivatives, U.S. Patent 4,226,866 to Christensen et al. In U.S. Patent 2,041,923, Hirata et al., 3-H and

A process for the preparation of 3-halo-1-carbacephalosporin is described, while Hatanaka et al., Tetrahedron Letters, Vol. 44, p. describes a process for the preparation of 3-hydroxy - (+/-) - 1-carbacephalosporin.

U.S. Patent No. 4,665,171, issued May 12, 1987 to Evans et al., Discloses cycloaddition of a chiral auxiliary and an imine [2 + 2] to produce a chiral azetidinone. More specifically, a 4 (S) -aryl-oxazolidin-2-one-3-yl-acetyl-halide, i.e. the chiral auxiliary, is reacted with an imine from a 3-aryl-acrolein (e.g., cinnamon aldehyde) from a benzylamine to form 3β- [4 (S) -aryl-oxazolidin-2-one-3-yl] -azetidin-2-one. The intermediates are characterized by a four membered nitrogen-containing ring to which is attached an N-benzyl group, a chiral auxiliary, and a -C2-R 'group (where R' is phenyl, furyl or naphthyl).

As described by Evans, intermediates are converted to 1-carbacephalosporins by a multi-step process. However, in order to be useful in the synthesis of carbacephems, the intermediates must first be modified by removal of the chiral auxiliary and the N-benzyl group by classic whip reduction. The compound thus obtained is re-acylated with phenoxyacetyl chloride and converted to the diazoketone and then to the enol key intermediate. Enol, in turn, is converted to loracarbef core by standard enol chlorination and side chain cleavage.

The Evans method is a useful synthesis method, but it has several disadvantages. The replacement of protecting groups is particularly undesirable. The chiral auxiliary is replaced by a V-side chain and the N-benzyl group is reduced to the NH function required for the key diazo group introduction reaction. The only known method for removing the chiral auxiliary group is whip reduction, but this method is incompatible with the 3-chlorocephem nucleus. The chemistry for the introduction of the diazo group depends on the use of rhodium catalyst, which is undesirable because of the cost and the negative impact on the environment.

B.G. Jackson and others, Synthesis of Carbacephem Antibiotics:

Synthesis Via Dieckmann Reaction Using Phenyl Esters to Direct the Regioselectivity of the Cyclization, Tetrahedron Letters, Volume 31, Volume 44, pp. 6317-6320. (1990) describe the synthesis of carbacephem using a modified Dieckmann cyclization. The Dieckmann process, however, depends on how the key amino acid mixture can be separated only by selective enzymatic acylation of the desired amino acid isomers. The resulting acylated product is converted to a key precursor which gives the enol by basic cyclization.

This achiral Dieckmann procedure has many undesirable features. As with the Evans method, the Dieckmann process requires the side chain to be replaced after the [2 + 2] cycloaddition reaction to form azetidinone. The solution limits the possible total yield because half of the key azetidinone intermediate has to be discarded. The need to replace the ester protecting groups (from methyl to p-nitrobenzyl) also increases the number of steps and reduces the efficiency of the process.

Therefore, a simplified chiral method was still needed for the preparation of carbacephems. The present invention satisfies this need by providing a chiral synthesis method, eliminating the need for side chain replacement and providing the desired nucleus in high yield. These methods and the novel β-lactam-containing intermediates have significant advantages over the prior art.

In order to facilitate the understanding of the principles of the invention, the following exemplary embodiments are described. However, it is to be understood that these are not intended to limit the scope of the invention and that, as is normally the case, those skilled in the art will be able to make changes, modifications and additional applications to the principles of the invention without departing from its spirit.

The present invention provides novel compounds and methods for easy preparation of cephalosporin analog compounds. The compounds and methods are particularly useful in the preparation of molecules containing the carbacephem nucleus, i.e., compounds known as 1-carba (1-detia) -3-cephem-4-carboxylic acids or as 1-carbacephalosporins or cephalosporin analogs of formula (Ia).

The invention is particularly useful in the preparation of 3-substituted derivatives such as 3-chloro-1-carba (1-detia) -3-cephem-4-carboxylic acids.

The present invention is based on a limited number of steps and high yield synthesis methods. The process uses a chiral auxiliary side chain that protects the

1-carbacephem-7-amino group, which remains unchanged throughout the synthesis. The 2-carboxy protecting group, which may be a methyl ester function or other group such as p-nitrobenzyl, may also be retained unchanged throughout the process. Surprisingly, it has been found that these protecting groups can be cleaved at a later stage of the reaction steps, which already produces the desired product.

This procedure combines the prior art of Evans and Dieckmann, but differs significantly from the use of protecting groups during the process ·· · · «*

- 6 do not change. In contrast to prior art, the chiral auxiliary group is present as a side chain up to the final step of carbacephem production. Until now, it has not been considered possible to remove the chiral auxiliary group from the carbacefem without removing most of the 3-substituted functions since whip reduction has been used to form the carbacefem core. The present procedure avoids this problem and the chiral auxiliary side and the methyl ester function may remain unchanged.

The compounds and methods of the present invention are exemplified by the following method. The synthesis begins with the preparation of the azetidin-2-one ester of formula (I), wherein RR ₂ and R 3 are as defined below. The oxazolidine moiety, also referred to herein as the Evans chiral auxiliary side chain, serves as an amino protecting group in the subsequent steps of the synthesis until cleaved at the end of the method. Similarly, during subsequent steps, the carboxy protecting group R _{2 is} also removed towards the end of the overall synthesis.

The azetidinone ester of formula (I) is obtained by cycloaddition of an imine ester of formula (I) wherein X 'is halogen and the imine ester of formula (2). The preparation of acetyl halide and similar imines, as well as the general cycloaddition process, are generally described in U.S. Patent 4,665,171, issued May 12, 1987 to Evans et al., The details of which are incorporated herein by reference.

The 2-vinyl azetidin-2-one ester of formula (I) is then hydrogenated to the 2-alkyl azetidin-2-one ester of formula (II). This compound of formula (II) is converted to 2-carboxylic acid (R _x = COOH) and then to 2-carboxylate (e.g. R _x =

CO ₂ Ph (where Ph is phenyl).

The cyclization of the 2-carboxylate is of formula (III)

4,6-Bicyclo compounds are obtained wherein R ₂ and R ₂ are the same as in the preceding compounds and X is hydroxy.

The 3-hydroxyl group is then replaced, for example, by a halogen atom, and the product is converted, for example, into the loracarbef nucleus of formula (IIIa).

One feature of the present invention is that both the amino protecting group (Evans chiral auxiliary group) and the carboxy protecting group can be cleaved off from the parent compound at a late stage in the synthesis. This contributes significantly to the efficiency and yield of the whole process.

Therefore, in the preferred method described below, the amino protecting chiral auxiliary and the carboxy protecting group are present during the formation of the azetidinone ester. Synthesis a

It undergoes the preparation of a 3-substituted bicyclic compound containing a 7-protected amino group and a 2-protected carboxy group, which is then converted to the carbacephem. Specific intermediates leading to the 3-substituted bicyclo compound can be accomplished by various routes and chemical methods, provided that the amino and carboxy protecting groups are retained in the 3-substituted bicyclo product. A preferred method of synthesis, for example, is described in I.

outline the reaction scheme.

As indicated above, the azetidin-2-one esters (3) are a 4 (S) -aryloxazolidin-2-one-3-ylacetyl halide of formula (1) and an imine of formula (2) is prepared by cycloaddition of [2 + 2] ester. The acetyl halide can be converted in situ to the corresponding homochiral ketene with a trialkylamine. Ketene and imine provide azetidinone by cycloaddition. Alternatively, ketene may be formed with anhydride of oxazolidinone acetic acid and trifluoroacetic acid or phosphoryl chloride or phosphonyl bromide or alkyl chloroformate.

In the 4 (S) -aryloxazolidin-2-one-3-ylacetyl halide of formula (19) used in the cycloaddition, R ₃ may be, for example, phenyl, (C 1 -C 4) alkylphenyl, halogenated phenyl - (C 1 -C 4) alkoxyphenyl, naphthyl, thienyl, furyl, benzothienyl or benzofuryl; and X 'is chloro, bromo, trifluoroacetoxy or -OP (= O) X''2 wherein X''is halogen. Oxazolidinone serves as an amino protecting group here and in the synthesis of any bicyclic compounds, such as those of formulas 7 and 8.

For example, the preparation of acetyl halide is described in U.S. Patent No. 4,665,171

This may be done according to the procedure described in Evans. The description is herein incorporated by reference. In summary, the acetyl halide is obtained from a 1-arylglycine which is first converted to the carbamate and then reduced to the 1-alcohol. The 1-al 9 alcohol is then cyclized to the (S) -4-aryloxazolidin-2-yl which is then N-alkylated with a halogenated acetic acid ester, the ester is saponified and the acid is converted to the acetyl halide.

The imine ester is represented by the formula (2) wherein it is 2-furyl, naphthyl, phenyl or 1,2- or 3-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, nitro. - phenyl substituted with carboxy, amido or halogen; and R ₂ is a carboxy protecting group such as methyl, p-nitrobenzyl, phenyl, C 1 -C 4 alkylphenyl, C 1 -C 4 alkoxyphenyl, halogenated phenyl, or other moieties which may be mentioned below. .

For example, the imine ester may be prepared as described in Evans Patent 4,665,171, which is incorporated herein by reference. For example, a 3-aryl acrolein is condensed in a suitable solvent with glycine having a protected carboxy group. Condensation occurs rapidly in the presence of desiccant or azeotropic distillation to remove water formed in the reaction.

By carboxy protecting group is meant a group which forms an ester with the carboxylic acid group. The quality of the carboxy protecting group used in the practice of the present invention is not critical if the carboxylic acid derivative is stable under the conditions of the subsequent reaction (s) elsewhere in the molecule and can be removed in a suitable next step without cleaving the remainder of the molecule.

For the protection of the carboxy substituents of these compounds, groups similar to the carboxy protecting groups used in cephalosporin, permicillin and peptide chemistry may be used. Preferred carboxy protecting groups are methyl and p-nitrobenzyl (PNB). Many other carboxy protecting groups are known in the art, such as benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl. -, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2 ', 4,4'- tetramethoxybenzhydryl, tert-butyl, tert-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4 ', 4''-trimethoxytrityl, 2- phenyl-prop-2-yl, trimethylsilyl, tert-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, β- (trimethylsilyl) ethyl, β - [di (-n-butyl) methylsilyl] ethyl, p-toluenesulfonic acid ethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1- (trimethylsilylmethyl) - prop-1-en-3-yl and the like. Further examples of this group are described in E. Hasiam, Protective Groups in Organic Chemistry, J.G.W. McOmie, Plenum Press ed. New York, N.Y., 1973. Chapter 5; and T.W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, NY, 1981, Chapter 5, see also U.S. Patent No. 4,734,494 (column 2, lines 56 to 3). Hirata and others).

It is desirable that the protecting group R ₂ remain attached to the molecule during subsequent operations, although it is an object of the invention to substitute the group R ₂ during the intermediate steps of synthesis. However, it is a further object of the present invention to remove the carboxy protecting group in its final cleavage step (s) during which the desired carbacephem is formed.

The present invention provides compounds that simultaneously contain both a Evans chiral amino protecting group and a R ₂ carboxy protecting group. Compounds of this type, such as azetidin-2-one esters, are particularly desirable because they allow the target compounds to be prepared in high yield and with fewer reaction steps. This advantage is further enhanced if these protecting groups remain in place throughout the synthesis process. Therefore, it is a particular feature of the present invention that both groups be present on the parent compound and remain in subsequent sequential steps such as hydrogenation, chlorination, and the like. during. In addition, as will be discussed below, it is a feature of the present invention that the removal of protecting groups in one or two steps (e.g., by reaction with trimethylsilyl iodide) greatly facilitates preparative life.

The 2-vinyl azetidin-2-one ester (3) thus obtained is then hydrogenated to give the 2-alkyl azetidin-2-one ester (4). Reduction of the vinyl double bond at the 2-position can be readily accomplished in solution by the introduction of hydrogen with soluble or insoluble hydrogenation catalysts such as Pd-carbon or other insoluble or soluble hydrogenation catalyst. This reaction is preferably carried out without cleavage of the carboxy protecting group R 2. In addition, the chiral auxiliary protecting group remains intact. Cleavage or substitution of these two groups is thus avoided and consequently the whole synthesis is simpler and more efficient.

The R-1 group is then converted to the carboxylic acid ester (5) according to formula (5) and then to the carboxylate ester (e.g. COOPh; where Ph is phenyl). These reaction steps may, for example, lead to the carboxylic acid via ozonolysis of the R-furyl group, which is then converted to the ester by reaction with, for example, phenol, triophenol, 1,3-dicyclohexylcarbodiimide and catalytic amount of 4-dimethylaminopyridine. These chemical methods are well known in the art and are described, for example, in B.G. Jackson and others describe Synthesis of Carbacephem Antibiotics: Synthesis Via Dieckmann Reaction Using Phenyl Esters to Direct the Regioselectivity of the Cyclization. in Tetrahedron Letters, Vol. 44, No. 6317-6320. p. (1990), which is incorporated herein by reference.

The cyclization of the diester (6) to the β-ketoester (7) is also accomplished by chemical methods known in the art. Jackson et al., Supra, Synthesis of carbacephem antibiotics c. In this publication, cyclization with lithium hexamethyldisilazide or potassium tert-butoxide in tetrahydrofuran at -78 ° C is described. Subsequent replacement of the 3-hydroxy group results directly in the desired 3-substituted (typically halogen substituted) compound of formula (8).

The synthesis is then followed by the amino protecting group and the carboxy13

continues with the removal of the protecting group. Preferred cleavage of the chiral auxiliary amino protecting group and the carboxy protecting group is the reaction with trimethylsilyl iodide (TMSJ). As shown in the following embodiments, these protecting groups protect the desired 7-amino and 2-carboxy substituents of the carbacephem product during the intermediate steps and are readily removed by the chemical method of trimethylsilyl iodide. However, with trimethylsilyl iodide, it is also possible to remove methyl or p-nitrobenzyl carboxy protecting groups and these have properties which make them particularly advantageous.

The conversion of the 3-position (e.g., chlorine)-substituted compound (8) to the carbacephem (9) is preferably carried out by the trimethylsilyl iodide chemical method. When the carboxy protecting group R _{2 is a} methyl group, the reaction with trimethylsilyl iodide cleaves both the chiral auxiliary group and the R 2 group to give the carbacephem (9). If the carboxy protecting group is not a methyl group, two alternative two-step routes can be followed. The preferred route is to cleave the carboxy protecting group, for example the p-nitrophenyl group, and obtain the 2-carboxylic acid. The reaction of the carboxylic acid with trimethylsilyl iodide then provides the carbacephem (9). Alternatively, the chiral auxiliary group may first be cleaved with trimethylsilyl iodide to yield the 7-amino compound, which is then converted to the carbacephem after removal of the carboxy protecting group.

Compounds of formulas I, II, and III having both a chiral auxiliary amino protecting group and a carboxy protecting tube port were previously unknown. These compounds allow the production of a variety of useful materials in high yields.

The present invention thus provides novel compounds of formula (I) wherein R1 is 2-furyl, naphthyl, phenyl, 1, 2 or 3, C1-C6 alkyl, C1-C6 alkoxy, Phenyl substituted with C 1-6 alkylthio, nitro, carboxy, amido or halogen, preferably 2-furyl. R ₂ may be hydrogen or a carboxy protecting group as defined above, and preferably methyl or p-nitrobenzyl. R ₃ is phenyl, (C 1 -C 4) alkylphenyl, halogenated phenyl, (C 1 -C 4) alkoxy-phenyl, naphthyl, thienyl, furyl, benzothienyl or benzofuryl, most preferably phenyl. As described in the examples, particularly preferred compound is a phenyl group represents furyl, R ₂ is methyl and R ₂ is wherein.

The present invention also provides compounds of formula II wherein R 1 is 2-furyl, naphthyl, phenyl, 1,2 or 3, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, Phenyl substituted with C 6 alkylthio, nitro, carboxy, carboxylic acid, amido or halo, or with a leaving carboxylic acid derivative. The leaving group as used herein refers to a substituent which is normally removed from a molecule by a chemical reaction. Carboxylate containing such a leaving group15

derivative can be a COOR 4 or COSRy formula compound having the formula of 0R ₄ or SR ₄ group of the leaving group of the formula wherein R ₄ is C 1-6 alkyl, C 2-6 alkenyl, phenyl, or 1,2 or Phenyl substituted with 3 substituents such as C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, nitro, carboxy, amido or halogen, or the like. Preferred R 1 groups are 2-furyl, carboxyl and phenyl carboxyl. R ₂ represents a carboxy-protecting group, preferably a methyl or p -nitrobenzil (PNB) group. R3 is phenyl, (C1-C4) -alkylphenyl, halogenated phenyl, (C1-C4) -alkoxyphenyl-naphthyl, thienyl, furyl, benzothienyl or benzofuryl, preferably phenyl. .

According to the following examples, the preferred compounds of formula II are as follows:

The compound is R _x R ₂ R 3

4a 2-furil methyl phenyl 4b 2-furyl PNB phenyl 4c 2-furyl H phenyl 5a COOH methyl phenyl 5b COOH PNB phenyl 6a COOPh methyl phenyl 6b COOPh PNB phenyl

Other novel compounds of the present invention include compounds of formula III wherein R ₂ is a carboxy protecting group as defined above, preferably methyl or p-nitrobenzyl or hydrogen. R3 is phenyl, (C1-C4) -alkylphenyl, halogenated phenyl, (C1-C4) -alkoxyphenyl, naphthyl, thienyl, furyl, benzothienyl or benzofuryl, preferably phenyl.

The 3-position X substituent is a substituent known to provide useful carbacephem compounds. More specifically, X is hydroxy, alkyl, (C1-C6) alkyl, (C1-C4) alkoxy, (C1-C4) alkylthio, trifluoromethyl, (C2-C6) alkenyl, (C2-C6) substituted alkenyl -, C 2 -C 6 alkynyl, C 2 -C 6 substituted alkynyl, phenyl, substituted phenyl, C 1 -C 6 alkoxymethyl, phenyl-C 1 -C 6 alkoxymethyl, tri (I). (C 6 -C 6) alkylsilyloxymethyl, trifluoromethylsulfonyloxy, nitrile, phenoxy or halogen.

By halogen we mean bromine, chlorine, iodine or fluorine. A C 1-4 alkoxy group such as methoxy, ethoxy, propoxy or butyloxy. 1-4 alkylthio groups include methylthio, ethylthio, tert-butylthio and the like.

C 1-6 alkyl groups include straight and branched chain alkyl groups such as methyl, ethyl, n-propyl, isopropyl, η-butyl, tert-butyl, η-pentyl, n-hexyl, 3-methyl- pentyl and similar alkyl groups. C 1-6 alkyl groups include C 1-6 alkyl substituted with cyano, carboxy, amino, C 1-4 alkoxy, C 1-4 alkylthio, trifluoromethyl, trifluoromethylthio or halogen. . Cyano substituted with C 1-6 alkyl means cyanomethyl, cyanoethyl, 4-cyanobutyl and the like; Carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl and the like under C 1-6 alkyl substituted carboxy; halogen · substituted C 1-6 alkyl by chloromethyl, bromomethyl, 2-chloroethyl, 1-bromomethyl, 4-chlorobutyl, 4-bromophenyl, chloro-hexyl, 4-fluoro-butyl, 3-fluoro-propyl, fluoro-methyl and the like; C 1-6 alkyl substituted with amino group refers to groups such as 2-aminoethyl, aminomethyl, 3-aminopropyl or 4-aminobutyl; C 1-6 -alkyl substituted with C 1-4 -alkoxy, methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, ethoxymethyl, 3-propoxypropyl, 3-ethoxybutyl,

4-tert-butyloxy-butyl, 3-methoxy-pentyl, 6-methoxy-hexyl and the like; C 1-6 -alkyl substituted with C 1-4 alkylthio, for example, methylthiomethyl, 2-methylthioethyl, 2-ethylthiopropyl, 4-methylthiobutyl,

5-ethylthiohexyl, 3-tert-butylthiopropyl and the like; C 1-6 -alkyl substituted by trifluoromethyl, for example 2,2,2-trifluoromethyl, 3,3,3-

-trifluoropropyl, 4,4,4-trifluorobutyl and the like; C 1-6 alkyl substituted with trifluoromethylthio, for example trifluoromethylthiomethyl, 2-trifluor

-methylthioethyl, 2-trifluoromethylthiopropyl, 4-trifluoromethylthiobutyl, 5-trifluoromethylthiohexyl and the like substituted C 1-6 alkyl.

C2-C6 alkenyl refers to a straight or branched chain olefinic group. Such C 2-6 alkenyl groups include ethenyl, 1-propenyl, 2-propen-1-yl, 1-buten-1-yl, 2-buten-1-yl, 3-butene-1 yl, 1-penten-1-yl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl,

1-hexen-1-yl, 2-hexen-1-yl, 3-hexen-1-yl, 4-hexen-1-yl, isopropen-1-yl, isobutenyl, isopentenyl, isohexenyl group and the like. A subset of C2-C6 alkenyl groups is a

C 3-6 alkenyl groups.

C2-6-substituted alkenyl means C2-6-alkenyl substituted with one or more halogen, hydroxy, protected hydroxy, nitro or trihalomethyl groups. It will be appreciated, of course, that during the process, the free hydroxy group must be protected as mentioned above. Preferred substituted

C2-C6 alkenyl groups include (Z) -3,3,3-trifluoro-1-propen-1-yl and (Z) -1-propen-1-yl.

C 2-6 alkynyl refers to straight or branched chain acetylene unsaturated groups. C2-6 alkynyl groups include, for example, ethynyl, 1-propin-1-yl, 2-propin-1-yl, 1-butyn-1-yl, 2-butyn-1-yl, 3-butine. 1-yl, 1-pentin-1-yl, 2-pentyl-1-yl, 3-pentin-1-yl, 4-pentin-1-yl, 1-hexin-1-yl, 2-hexin-1-yl, 3-hexin-1-yl, 4-hexin-1-yl, 5-hexin-1-yl, 2-methyl-2-propin-1-yl, 2 -methyl-4-propin-1-yl, 219

methyl-3-pentin-1-yl, 2-methyl-3-pentin-1-yl, 2-methyl-3-butin-1-yl, and the like.

Substituted C2-C6 alkynyl means C2-C6 alkynyl substituted by one or more halogen, hydroxy, protected hydroxy, nitro or trihalogenated methyl groups.

C 1-6 alkyloxymethyl groups include, for example, methyl oxymethyl, ethyloxymethyl, η-propyloxymethyl, n-butyloxy.

-methyl, n-pentyloxymethyl, n-hexyloxymethyl, isopropyloxymethyl, isobutyloxymethyl, isopentyloxymethyl, isohexyloxymethyl and the like. Examples of phenyl (C1-C6) -alkyloxymethyl groups include benzyloxymethyl, (2-phenyl) -ethyloxy-

-methyl-, (3-phenyl) -n-propyloxymethyl, (4-phenyl) -n-butyloxy- -methyl-, (4-phenyl) -n-butyloxymethyl, (5-phenyl) -n-pentyloxy- -methyl-, (6-phenyl) -n-hexyloxymethyl, (2-phenyl) - (2-methyl) ethyl-

oxymethyl, (3-phenyl) - (3-methyl) -n-propyloxymethyl and the like.

Substituted phenyl substituted with one of the substituents a and / or '- wherein a and a' are independently hydrogen, halogen, hydroxy, C 1-4 alkoxy, C 1-4 alkanoyloxy, C 1-4 alkyl, C 4 -C 4 alkylthio, amino, mono- or di (C 1 -C 4) alkylsulfonylamino, carboxy, carbamoyl, hydroxymethyl, aminomethyl or carboxymethyl groups substituted phenyl. Examples of substituted phenyl groups include halogenated phenyl groups such as 4-chlorophenyl, 3-bromophenyl, 2-fluorophenyl, 2,4-dichlorophenyl and 3,5-dichlorophenyl; hydroxyphenyl20 groups such as 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,4-dihydroxyphenyl and 3,4-dihydroxyphenyl; alkoxyphenyl groups such as 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 3,4-dimethoxyphenyl, 4-tert-butyloxyphenyl, 4-methoxy -3-ethoxyphenyl and 4-n-propoxyphenyl; alkanoyloxyphenyl groups such as 2-acetoxyphenyl,

4-propionoxyphenyl, 4-formyloxyphenyl, 4-acetoxyphenyl,

3-butyryloxyphenyl and 3-acetoxyphenyl; alkylphenyl groups such as 4-methylphenyl, 2-methylphenyl, 2,4-dimethylphenyl, 3-tert-butylphenyl,

4-ethylphenyl, 4-ethylphenyl, 4-ethyl-3-methylphenyl and 3,5-dimethylphenyl; alkylthiophenyl groups such as 4-methylthiophenyl, 3-n-butylthiophenyl, 2-ethylthiophenyl, 3,4-dimethylthiophenyl and 3-n-propylthiophenyl -group; aminophenyl groups such as 2-aminophenyl, 4-aminophenyl, 3,5-diaminophenyl and 3-aminophenyl; alkanoylamino groups such as 2-acetylamino, 4-acetylamino, 3-propionylamino and 4-butyrylamino; alkylsulfonylamino groups such as 3-methylsulfonylamino, 4-methylsulfonylamino, 3,5- (dimethylsulfonylamino) phenyl, 4-n-butylsulfonyl; aminophenyl and 3-ethylsulfonylaminophenyl; carboxyphenyl groups such as 2-, 3- or 4-carboxyphenyl, 3,4-dicarboxyphenyl and 2,4-dicarboxyphenyl; carbamoylphenyl groups such as 2-carbamoylphenyl, 2,4-dicarbamoylphenyl and 4-carbamoylphenyl; hydroxymethylphenyl groups such as 4-hydroxymethylphenyl and 2-hydroxymethylphenyl; aminomethylphenyl groups such as 2-aminomethylphenyl and 3-aminomethylphenyl; and carboxyphenyl groups such as 2-carboxymethylphenyl, 4-carboxymethylphenyl and 3,4-dicarboxymethylphenyl; and substituted phenyl groups having various substituents such as 4-chloro-3-methylphenyl, 4-fluoro-3-hydroxyphenyl, 3,4-dichloro-4-hydroxyphenyl, 4-hydroxy-3 -chlorophenyl, 4-hydroxy-3-methylphenyl, 4-ethyl-3-hydroxyphenyl, 4-methoxy-3-hydroxyphenyl, 4-tert-butyloxy-2-hydroxyphenyl -, 4-acetylamino-3-methoxyphenyl, 3-amino-4-ethylphenyl, 2-aminomethyl-4-chlorophenyl, 2-hydroxymethyl-3-methoxyphenyl -, 2-hydroxymethyl-4-fluorophenyl, 2-acetoxy-4-aminophenyl, 4-acetoxy-3-methoxyphenyl, 3-isopropylthio-4-chlorophenyl, 4-. acetoxy-3-methoxyphenyl, 3-isopropylthio-4-chlorophenyl, 2-methylthio-4-hydroxymethylphenyl,

4-carboxy-3-hydroxyphenyl, 4-ethoxy-3-hydroxyphenyl, 4-methylsulfonylamino-2-carboxyphenyl, 4-amino-3-chlorophenyl, and 2-carboxylic acid. carboxy-methyl-4-hydroxy-phenyl.

As shown in the following examples, the preferred compounds of formula III are:

The compound number ^R 2 r ₃ X 7a methyl phenyl OH 7b PNB phenyl OH 8a methyl phenyl cl 8b PNB phenyl cl 8c H phenyl cl

Carbacephems prepared by the methods of the present invention are useful intermediates for the preparation of various acylated compounds, such as cephalosporin analogues useful as antibacterial agents, see, for example, U.S. Patent 4,335,211, June 15, 1982 to Hashimoto et al. and U.S. Patent No. 4,734,494 issued March 29, 1988 to Hirata et al., incorporated herein by reference. Conversion to analogous compounds may be accomplished by conventional means, for example, by selective acylation as described in Hashimoto, U.S. Patent 4,335,211.

The following examples illustrate compounds and methods of the present invention. However, these examples are for illustrative purposes only and are not intended to limit the scope of the invention.

Preparation of carbacephems using a methyl carboxy protecting group

Compositions and methods using the methyl group as a carboxy protecting group are illustrated in Figures 1-7. examples. The reaction steps are illustrated in Table II. outline the reaction scheme.

Example 1

The amount of acid chloride of formula (Ia) is about 325 mmol

After cooling to -40 ° C, 2 molar equivalents (90.4 mL, 650 mmol) of triethylamine (TEA) were added dropwise over 20 minutes. The mixture was stirred for one minute and Schiff's base methyl ester solution 2a (63 g, 326 mmol ester in 360 mL dichloromethane) was added over 25 minutes. Then, for an additional 60 minutes, the thermometer showed the product at 6.15 minutes. The hydrogenated (reduced) product of Formula 4a showed about 1% of the UV absorbance of the starting material at 254 nm and gradually showed disappearance of the starting material. One drop of the filtered solution was diluted with 1 mL of acetonitrile / water / phosphoric acid (50/50 / 0.2%). HPLC showed a clear reduction over about 7.5 hours. The Pd / C catalyst was filtered through a washed Hyflo pad and cooled overnight. The methylene chloride was evaporated to a syrup (212 g) which was inoculated for crystallization. The crystals were slowly slurried with 400 mL of ethyl ether, then the crystalline slurry was filtered and washed with 200 mL of ethyl ether. The first product (A) was dried in vacuo at 50 ° C to give 101.0 g (78%) of product. The filtrate was concentrated to an oil (27.5 g) which was crystallized with ethyl ether and inoculated. The product (B) was filtered off with ethyl ether to give 2.9 g (2.2%) of product. The overall yield of the two steps was about 80%. Concentrated samples (A) and (B) were analyzed by HPLC in acetonitrile / water / phosphoric acid (44/56 / 0.2%) to give high peaks for product 4a. The infrared (IR) analysis showed at 1758.9 cm ^_1 βlaktámot. At 589 nm (CHCl3), the specific rotation was + 55.89 °.

Elemental analysis according to the formula ^C 21 ^H 22 ^N 2 ° 6:

date: C: 63.31; H: 5.57 N 7.03%; found: C: 63.08. H: 5.37; N 7.00 NMR (CDCl 3), δ:

1.72 (m, 2), 2.64 (t, 2), 3.48 (d, 1), 3.68 (s, 3), • 9 · ·· * »♦ · * ·. · * · • · ♦ · «« «·

3.91 (Q, 1). 4.26 (D, 1), 4.30 (dd, 1), 4.64 (d, 1), 4.72 (T, 1), 4.94 (Dd, 1.) , 5.98 (d, 1). 6.29 (dd, 1) 7.30 (D, 1), 7.40 (s, 5).

Example 2b

A portion of the 2 + 2 product of Formula 3a, which was isolated in solid form, was hydrogenated again at room temperature and atmospheric pressure with about 2% by weight of Pd / C catalyst (as described in Example 2a). The reaction mixture contained 110 g (277 mmol) of methyl ester 3a in 1100 mL of dichloromethane and 2.2 g of 5% Pd / C catalyst. The mixture was carefully degassed using a gentle vacuum (until dichloromethane began to boil), closing the vacuum, opening the hydrogen valve, and repeating these operations before starting the hydrogen delivery. HPLC in methanol / water clearly showed the starting material consumed in 6.15 hours. The product was only slightly absorbed under UV light (up to about 1/100 of the starting material) and therefore appeared in tiny marks on the HPLC chromatogram. The Pd / C catalyst was filtered on Hyflo, washed with methylene chloride (200 mL) and concentrated to a syrup (206 g). This syrup was quickly diluted with 60 mL of ethyl ether and stirred with a magnetic stirrer for crystallization. Ethyl ether (340 mL) was added slowly and the mixture was filtered and washed with ethyl ether. The precipitate (4a) was dried under vacuum at 50 ° C to 86.6 g of (A). The yield was about 78.5%. After standing at room temperature for 3 days, the filtrate was decanted from an oily precipitate and evaporated to 227 g of crystals and oil * ··································• · - · · ··

- 26 in. This material was slurried in 50 mL (3/1) ethyl ether / isopropyl alcohol and filtered and washed with the same solution. Product B (4a) had a dry weight of 1.5, a yield of about 1.4%, and a total yield of the isolated material of about 80%. The NMR of product (A) and (B) in CDCl3 was consistent with the desired product.

Example 3

The conversion of the furan (4a) to the carboxylic acid (5a) was performed by ozonolysis. To 7.97 g (20 mmol) of furan 4a (144 mmol) were added dichloromethane (144 mL) and methanol (16 mL) and the mixture was cooled to -65 ° C with dry ice. Ozonolysis was continued by introducing ozone for 4 minutes, 4 minutes after the appearance of a blue color indicating excess ozone. The excess ozone was purged with oxygen followed by nitrogen. 6.8 ml of a 30% solution was added, the cooling bath was removed, and the mixture was warmed to room temperature over 30 minutes. After about 2 hours at room temperature, HPLC showed good ozonolysis. The mixture was washed with brine (2 x 150 mL) and allowed to stand at room temperature overnight. The solution was treated with sodium hydrosulfite solution (1.04 g, 10 mmol) and stirred until a negative reaction with iodine starch paper was obtained. Sodium sulfate was added for drying. Sodium hydrosulfite and sodium sulfate were filtered off and the solution was evaporated to 9.2 g of a foam which crystallized after addition of 25 ml. The crystallization mixture was diluted with 3 volumes of ethyl ether and stirred for 2 hours. 25 ml

1: 4 Ethyl acetate: Filtration with ethyl ether and ethyl ether: ··· ♦ «9 9 9 9 9 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 after washing with a white solid

form 6.35 g (5a) carboxylic acid we got. THE mining 84%. NMR (CDCl 3 ), δ: 1.58 (m, 1), 1.81 (m, 1), 2.38 (t, 2), 3.64 (D, 3.71 (s, 3), 3.94 (m, 1), 4.28 (d, 1), 4.34 (Dd, 1), 4.69 (D, 1), 4.77 (t, 1), 5.04 (dd, 1), 7.43 (S, 5). Elemanalíz is ac ₁₈ h ₂₀ n ₂ O _{7 is a} formula; my father: date: C: 57.4 4, H: 5.37, N: 7.44 %; found: C: 56.8 4, H: 5.35, N, 7.04 %.

1),

Example 4 was carried out so that 39 g (103.6 mmol) of the carboxylic acid 5a was

It was cooled to 0 ° C in 323 mL of dichloromethane. TEA (14.43 mL, 103.6 mmol) was added dropwise and the mixture was cooled to -30 ° C.

thereafter

Dimethylaminopyridine (DMAP) (2.53 g, 20.7 mmol) was added followed by phenyl chloroformate (17 mL, 139.2 mmol). The bath temperature was then maintained at 0 ° C for 20 minutes. 1N Hydrochloride (124 mL) was added and the solution was stirred until it reached room temperature. The acidic wash was separated and HPLC showed the presence of DMAP and some phenol. The solution was washed with 200 mL water, which removed residual DMAP and some phenol. It was then washed with 2 x 200 ml of sodium chloride solution and dried over magnesium sulfate. HPLC analysis showed that the product was 74% of 6a and 4 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · It contained about 6% phenol. The product also contained three minor amounts of impurities but did not contain any starting material. The solution was concentrated to an oil (53 g) and placed in a refrigerator overnight and used in the next ring closure reaction (Example 5a).

Example 5a

The Dieckmann reaction was carried out with 46.9 (103.6 mmol) of the oil of Example 4 with a solution of 536 mL of tetrahydrofuran.

Sodium terepentoxide (45.6 g, 414.4 mmol) was added. After the ester (6a) was added at -78 ° C, the mixture was stirred for 20 minutes and 518 ml of 1N hydrochloric acid was added. The exothermic reaction raised the temperature of the mixture to -5 ° C and stirred for 5 minutes at pH 2 until it reached 0 ° C. 518 ml of sodium chloride solution were added and the organic phase was separated. The aqueous phase was extracted with dichloromethane (322 mL). The organic extracts were combined and a little more aqueous phase evolved. This material was evaporated to a volume of about 500 ml in a rotary evaporator, washed with 100 ml of sodium chloride solution and dried over sodium sulfate. The product crystallized during drying, and therefore the sodium sulfate was filtered off with methylene chloride washing. 200 ml of 2-butanol were added and the resulting mixture was concentrated to about 300 ml. Product crystallized. An additional 200 mL of 2-butanol was added and the mixture was stirred for ca. It was concentrated to 400 g of slurry. 2-Butanol (100 mL) was added and the mixture was concentrated to a slurry of about 427 g, filtered at room temperature and washed with 2-butanol (100 mL) followed by ethyl ether. This product is vacuum at 40 ° C overnight ··· ♦

V * • · ν · ···· · kV »· · · · · · · · · · · · · · · · · · · · · · · · · · · · ·. which corresponds to a 65% (uncorrected) yield of the two reactions. The HPLC analysis of product (A) was excellent. The filtrate and washings were placed in a refrigerator overnight, the product (B) was filtered and washed with 2-butanol and ethyl ether. The filtrate contained more crystals, so product (C) was filtered and the off-white crystals were dried. 1.50 g of additional product were obtained, corresponding to an additional 4% yield. Product (B) was a sticky brown substance, so it was suspended in THF (30 mL), 2-butanol (60 mL) was added and the mixture was evaporated. The crystals were gummy, so the 2-butanol was evaporated to give a gum which was replaced nicely with 20 mL of ethyl acetate. The ether made the product gummy, so it was filtered off from ethyl acetate and washed with 10 ml of ethyl acetate. The resulting product was dried at 40 ° C in vacuo to give 0.72 g of product (D), giving an additional 2% yield. The yield of the isolated material was 71%. The HPLC analysis of product (C) and (D) was good. NMR (CDCl ₃ ), δ:

1.52 (m, 1), 1.85 (M, 1), 2.33 (m, 2), 3.65 (m, 1) 3.84 (s, 3), 4.32 (Dd, 1), 4.68 (d, 1) , 4.74 (t, 1), 5.02 (dd, 1), 7.40 (m, 5), 11, 28 (s, 1) -

Example 5b

The Dieckmann ring closure reaction for the formation of the enol (7a) was carried out in 0.45 g (1.0 mmol), 0.93 g (2.1 mmol), 55% in 0.45 g (1.0 mmol) of phenyl ester 6a in of sodium hydride and 0.19 ml (2 mmol) of the volume of 30 W · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · to to · · ·· * ··

-butanol. A slow reaction to produce tertiary butoxy (") - Nail raised the temperature to 28 ° C. Ring closure took less than 20 minutes. At 30 minutes, the reaction mixture was quenched by the addition of excess acetic acid (0.29 mL, 5 mmol), showing very little heat evolution. After stirring for 5 min, 10 mL of 2-butanol was added and the mixture was concentrated to a slurry of 6.2 g (about 5 mL). Water (1 mL) was added to dissolve any Na-acetate (1), and the mixture was stirred at room temperature for 1 hour and filtered. The precipitate was then washed with 8 ml of a 5: 1 mixture of 2-butanol: water and then with water. Filtration was slow. The cream colored product 7a was dried at 45 ° C for 24 hours to give 0.25 g. The weight yield was about 70%. HPLC analysis of 7a only showed traces of phenol.

NMR (CDCl ₃ ), δ:

1.50 (m, 1), 1.84 (M, 1), 2.31 (m, 2), 3.64 (m, 1) 3.84 (s, 3), 4.31 (Dd, 1), 4.68 (d, 1.) , 4.74 (t, 1), 5.02 (dd, 1), 7.39 (m, 5), 11.27 (s, 1).

Example 6

Phosphite / chlorine reagent was prepared by mixing 25 ml of dichloromethane and 75 ml of ethyl acetate, the solution was cooled to -35 ° C and 5.26 ml (20 mmol) of triphenylphosphite and chlorine gas were added simultaneously. solution. A colorless solution was obtained. To this solution was added pyrimidine (1.57 mL, 20 mmol) causing an immediate precipitate, followed by enol (7a) dissolved in CH 2 Cl 2 (3.58 g, 10 mmol). The temperature rose to 23 ° C in less than 5 minutes. The mixture was stirred for 6.5 hours and HPLC analysis showed very little, about 4% residual enol. The ester product to acid product ratio was about 3.5: 1. Methanol (10% v / v) was added to convert the acid chloride or anhydride (indicated by the appearance of an acid product on the HPLC chromatogram if the sample stood for 15 minutes) to the methyl ester and the conversion was complete within 30 minutes. Dichloromethane (100 mL) was added to facilitate separation of the layers, and the organic layer was washed with 1 N hydrochloric acid (2 x 100 mL) and brine. The resulting material was dried over sodium sulfate and evaporated to a residue of 11.6 g. The product was crystallized by adding 40 ml of methyl tert-butyl ether (MTBE), heating to reflux and stirring overnight at room temperature. The product was filtered off, washed with 25 ml of methyl tert-butyl ether and dried at 45 ° C for 4 days. 3.60 g of butter is a solid (8a)

we got a product, yield 69% volt. The filtrate was HPLC analysis is also some product Who. NMR (DMSO-d6), δ: 1.97 (m, 2), 2.57 (m, 2), 3.70 (s, 3), 3.78 (m, 1)

4.10 (dd, 1), 4.49 (d, 1), 4.71 (t, 1), 5.00 (dd, 1), 7.38 (m, 5).

Example 7

This method illustrates a key step of the present invention. Both the methyl ester and the chiral auxiliary side chain are cleaved by reacting the methyl ester product (8a) with trimethylsilyl iodide (TMSJ). To 0.377 g (1 mmol) of methyl ester (8a) and 3.8 mL of acetinitrile (ACN), 2.5 equivalents (0.53 mL) of hexamethyldisilazane (HMDS) and 2.5 equivalents of Trimethylsilyl iodide (36 mL) was added and the reaction mixture was refluxed at about 80 ° C. After 1/2 hour, the saponification occurred in about 30% and the opening of the oxazolidinone ring occurred in about 66%. After 4 hours, the saponification was almost 50% and the opening of the oxazolidinone ring was approximately 57%. In this way, the saponification slowed down but the oxazolidinone appeared to be re-formed as the trimethylsilyl iodide was consumed. The mixture was refluxed overnight and after 22 hours the saponification was 78% and most of the oxazolidinone was recovered. An additional equivalent amount of trimethylsilyl iodide was added and after 1 hour, the saponification occurred at 85% and many oxazolidinones were opened. After another 2 3/4 hours, the saponification was 87%. One equivalent of hexamethyldisilazane and trimethylsilyl iodide was added and after 1 hour the saponification rate was 90% and after 2 1/3 hours it was 92%. Another equivalent of each reagent was added to the reaction mixture, and after 1 hour, about 95% of the saponification occurred and 77% of the reagent appeared to have an oxazolidinone ring open. After cooling to 5 ° C, 0.504 g (4.5 mmol) of 1,4-diazabicyclo [2.2.2] octane (DABCO) was added to the reaction mixture, which was stirred overnight at room temperature. HPLC analysis after about 15 1/2 hours showed an excellent enamine reaction. Concentrated hydrochloric acid (0.29 mL of hydrochloric acid in 1.61 mL of water) was added to dissolve the DABCO-hydrogen iodide complex and the product of Formula 9a crystallized. The pH of 5.2 was lowered to 4.0 with 3 drops of concentrated hydrochloric acid. After stirring for 10 minutes, the precipitate was filtered off and washed with 16 mL of 2: 1 acetonitrile: water followed by 5 mL of ethyl acetate. The material was dried at 50 ° C in vacuo to give 0.155 g of an off-white solid 9a. HPLC analysis revealed 98% product, corresponding to a crude yield of 71%.

NMR (DMSO-dg TFA), δ:

2.00 (m, 2), 2.68 (m, 2), 3.95 (m, 1), 4.84 (d, 1),

8.88 (sz, 5).

Although this is not assured with certainty, it is believed that the reaction of trimethylsilyl iodide with the methyl ester (8a) is carried out according to Scheme Ha.

As can be seen, the reaction of the methyl ester (8a) with trimethylsilyl iodide, hexamethyldisilazane and acetonitrile provides the open oxazolidinone ring product in the form of the iodoethyl intermediate (8a '). Addition of 1,4-diazabicyclo [2.2.2] octane removes the iodine substituent and (8a '') enamine is formed. Finally, the addition of aqueous hydrochloric acid to the carbacephem of formula 9a, namely (6R, 7S) -7-amino-3-chloro-1-azabicyclo [4.2.0] oct-2-en-8-one-2-carboxylic acid leads.

A weak, non-nucleophilic base or hydrogen iodide scavenger is added together with the trimethylsilyl iodide to prevent extensive degradation of the β-lactams. A preferred base is hexamethyldisilazane, i.e. 1,1,1,3,3,3,3-hexamethyldisilazane. This plays a more important role by silylating any carboxylic acid that may be present and by binding to the hydrogen iodide formed, not deactivating dea trimethylsilyl iodide. Another successful non-nucleophilic base is pyridimidine. Stronger bases such as triethylamine are unsuitable because they are too complexing with and deactivating trimethylsilyl iodide. Alternatively, allyl trimethylsilane can be used as the hydrogen iodide trapping agent and the silylating agent (the reaction results in trimethylsilyl iodide).

The preferred base used for the removal of hydrogen iodide from iodoethyl intermediate is 1,4-diazabicyclo [2.2.2] octane, i.e. 1,4-diazabicyclo [2.2.2] octane. Simple amine bases such as triethylamine are ineffective. Other diazabicyclo bases such as DBU (1,8-diazabicyclo [5.4.0] undec-7-ene) and DBN (1,5-diazabicyclo [4.3.0] non-5-ene) are also useful. However, they are

They are more potent than 1,4-diazabicyclo [2.2.2] octane and cause greater epimerization at the 7-position of the δ-lactam. Preparation of carbacephem using a non-methyl carboxy protecting group

As another example, an alternative synthetic process is described using p-nitrobenzyl (PNB) ester as the carboxy protecting group. As will be seen below, the use of a non-methyl ester slightly alters the synthesis technique but maintains the advantage of retaining the chiral auxiliary amino protecting group until the late stage of the process. This makes the process much more efficient and results in high yields. Refer to Figures 8-15f for details. The procedure described in Examples 1 to 4 is carried out according to Scheme III.

Example 8

This process is carried out in the same manner as described in Examples 1 and 2 until the methyl ester 4a is prepared. The methyl ester was then converted to the p-nitrobenzyl ester as follows. To the methyl ester 4a (180 g, 452 mmol) was added tetrahydrofuran (2500 mL) and cooled to 0 ° C. Water (452 mL) was added followed by dropwise addition of 1N sodium hydroxide (452 mL) over 10 minutes. HPLC analysis about 2 minutes after the addition of the base showed about 4% of the peak that could be the starting material and 75.7% of the peak of the product. After stirring for 15 minutes, the pH was lowered to 8.5 with 15% sulfuric acid. The tetrahydrofuran was evaporated in a rotary evaporator and the volume was quenched with water to an initial volume of 1600 ml.

An aliquot of 25 ml of 1600 ml was taken up in methylene chloride, 100 ml of ethyl acetate, 50 ml of saturated sodium bicarbonate solution and 100 ml of water. The bicarbonate extract was separated and washed with 25 mL of ethyl acetate. Ethyl acetate (50 mL) was added and the pH was adjusted to 2.0 with concentrated hydrochloric acid. The organic layer was separated, washed with brine and dried over sodium sulfate, and then concentrated to 16.5 g of slurry. This slurry was diluted with 15 mL of ether and the acid product 4c was filtered, washed with ether and dried in vacuo to give 0.96 g of product (A). Evaporation of the filtrate to dryness gave 0.15 g of product (B).

To the remainder of the reaction mixture were added methylene chloride (2500 mL), p-nitrobenzyl bromide (102.5 g, 474 mmol; 5% excess) and tetrabutylammonium bromide (TBABr) (29.1 g). The pH was 9.5 and the temperature was about 23 ° C. HPLC analysis after 1 hour indicated that the reaction was normal. The mixture was stirred overnight at room temperature and HPLC analysis indicated the reaction was complete. The aqueous phase was separated and washed with dichloromethane (100 mL). The combined methylene chloride solution was washed with 1600 mL of 10% sodium chloride solution and dried over magnesium sulfate. The resulting mixture was filtered through Hyflo, and dichloromethane was evaporated to a crystallizing syrup, which was slowly diluted with 2000 mL ethyl ether and 2000 mL isopropyl alcohol. The product was filtered, washed with 3: 1 ethyl ether: isopropyl alcohol and dried under vacuum at room temperature (50 ° C for the first two hours). 212.8 g of product (C) were obtained, which corresponds to a yield of 90.6% (aliquot sample for the supply of the acid product was not taken into account). The filtrate was allowed to evaporate into a syrup in a large crystallization dish, which was suspended in 100 ml of isopropyl alcohol, filtered and washed with isopropyl alcohol. The resulting material was dried at 50 ° C to 5.68 g (D) in vacuo, yielding an additional 2.4%. The total yield was about 218.5 g, or 93%, which is an excellent conversion to the p-nitrobenzyl ester of formula 4b. The NMR spectrum of product (C) was completely clear. HPLC analysis of product (C) showed 98.9% purity and product (D) showed 97.8% purity. HPLC analysis of the acid (A) showed 97.6% purity. NMR in deuterated dimethyl sulfoxide (DMSO) showed excellent results (with some water and ether present only). Product (A) m.p. 191-192 ° C; 143.5-144.5 of product (C); and product (D) was 142-143 ° C.

The FD mass spectrum of acid product (A) was 384 P. Titration in 66% dimethylformamide gave pKa = 5.8. Specific rotation at 589 nm was + 47.69 ° and at 365 nm + 138.28 ° in chloroform solvent. The ultraviolet spectrum measured in ethanol showed no greater absorption up to a rise starting at about 235 nm, which had a peak at about 200 nm. Elemental analysis data were as follows:

calculated: C: 62 .49, H: 5 >, 24, N: 7.29 %; found: C: 62, , 62, H: 5 >, 24, N: 7.18 %. NMR (dMSO-d6), δ: 1.81 (M, 1), 1.95 (m, 1), 2.63 (t, 1), 3.79 (Q, 1), 3.95 (D, 1), 4.12 (dd, 1), 4.25 (d, 1), 4.26 (D, 1.) 4.70 (T, 1), 4.97 (dd, 1), 5.23 (s, 2), 6.06 (D, 1.) 6, 32 (T, 1), 7.39 (m, 5), 7.49 (s, 1), 7.60 (D, 2), 8, 16 (D, 2).

Infrared spectrum analysis for ester product (C)

1759.5 cm ^x showed β-lactam. The ultraviolet spectrum showed a peak at 264 nm (ε = 9990). The specific rotation at 589 nm in CHCl3 was + 43.91 °. The FD mass spectrum had a P value of 519.

Elemental analysis based on the formula C ^ H ^ N ^ Og:

date: C: 62 42, H: 4.85; N: 8, 09%; found: C: 62 60, H: 4.91 N: 8, 17%. NMR (DMSO-d6), δ: 1.81 (M, 1.) , 1.95 (m, 1), 2.63 (t, 1), 3.79 (Q 1), 3.95 (D, 1.) , 4.12 (dd, 1) , 4.25 (d, 1), 4.26 (D, 1.) 4.70 (T, 1.) , 4.97 (dd, 1) , 5.23 (s, 2), 6.06 (D, 1.) 6.32 (T, 1.) , 7.39 (m, 5), 7.49 (s, 1), 7.60 (D, 2), 8, 16 (D, 2.)

Example 9

The conversion of the furan PNB ester (4b) to the carboxylic acid (5b) by ozonolysis was carried out as follows. To the furan PNB ester (66.0 g, 127 mmol) at room temperature was added methylene chloride (834 mL) and methanol (126 mL) and cooled with dry ice / acetone. During cooling, the mixture was purged with nitrogen. The ozonator was operated at 1.5 A and the O ₂ flow rate was set to 5 SCFH (0.14 atm valve position). The ozonator was started and the Og stream was introduced into the reaction solution. Dichloromethane (166 mL) was added over 2 minutes to dilute. Final blue coloration approx. We got it in 2 hours. The ozone inlet was replaced by purging with nitrogen to remove excess ozone (the blue coloration disappeared). The dry ice bath was removed and a room temperature water bath was used. 30% Hydrogen Peroxide (43.2 mL, 380 mmol) was added rapidly dropwise and the resulting mixture was stirred at room temperature for about 2.5 hours. HPLC analysis indicated a slow conversion of the intermediates to the acid product 5b. The mixture was cooled with a solution of 55 g of sodium hydrosulfite in 1000 ml of water until a negative iodine starch test result was obtained. This required almost the entire solution. HPLC showed 83% product. The dichloromethane layer was separated, washed with 5% sodium chloride solution (3 x 500 ml) and dried over magnesium sulfate. After cooling overnight, the mixture was filtered on a Hyflo and evaporated to a 1: 1 slurry of gelatinous methylene chloride. The material was slowly diluted with 900 mL of ether, stirred for 2 hours and filtered. The white solid was washed with ether and dried in vacuo to give 61.5 g of 5b. The HPLC analysis yield was 89.4% which corresponds to a yield of about 87%.

M.p. 78-81 ° C. NMR (in CDCl 3) was excellent.

NMR (CDCl ₃ ), δ:

1, 62 (M, 1), 1.86 (M, 1), 2.36 (t, 2), 3.76 (d, 1), 3.92 (Q, 1), 4.34 (D, 1), 4.34 (dd, 1) , 4.64 (d, 1) 4.77 (T, 1). 5.02 (Dd, 1.) , 5.22 (s, 2) , 7.43 (s, 5) 7.50 (D, 2), 8.22 (D, 2).

Example 10

The carboxylic acid product (4.48 g, 9 mmol) was added to dichloromethane (28 mL) and cooled to -30 ° C. Then, triethylamine (1.27 mL, 9.13 mmol, 1.01 equivalent) followed by 0.22 g (1.8 mmol) of dimethylaminopyridine was added, followed by phenyl chloroformate (1.52 mL, 12.1 mmol) in methylene chloride (7 mL) and stirred for 20 min. diester product and about 2% starting material, which did not change even after heating to 0 ° C. Three drops of triethylamine were added but no effect was obtained with 10.5 ml of 1N hydrochloric acid (10.5 mmol). After dilution and stirring to room temperature, the product was separated, washed with brine and dried over magnesium sulfate. ethyl acetate e The mixture was evaporated until the product crystallized at a volume of about 15 ml. After about 8 mL of ether was added, the crystals were sticky, so an additional 13 mL of ethyl acetate was added to the ether. The mixture was evaporated to a wet solid, slurried with isopropyl acetate (iPrOAC) (20 mL) and ethyl ether (40 mL) was added slowly. After filtration and washing with 20 ml of the same solvent mixture, the crystals were dried at 35 ° C in vacuo to give 4.11 g of a white solid (A). The yield was 80%. The filtrate was evaporated to a solid (1.3 g), slurried in ethyl ether (100 mL) and kept at room temperature overnight. This material was filtered and washed with 50 ml of ethyl ether to give 0.68 g of product (B). The yield was 13%. HPLC analysis of product (A) showed 94% purity and product (B) showed 85% purity. The total yield of the isolated product (without correction) is about 93%. NMR (in CDCl 3) showed excellent results (trace amounts of iPrOAC). The FD mass spectrum at 573 showed the parent product, but at 646 it probably also showed material from recombination of the degradation product. The specific rotation (methylene chloride, MeOH) was + 46.66 at 589 nm. The UV peak was at 264 nm and the e value was 10400. 115-118 ° C. The infrared spectrum (in methylene chloride) showed β-lactam at 1758 cm- ¹ .

Elemental analysis based on the formula C3QH27N3O9:

date: C: 62 62, H : 4.75, N 7 33 %; found: C: 62 65, H : 4.70, N 7 37 %. NMR (CDCl ₃ ), δ: 1.74 (m, 1) , 1.93 (m, 1), 2, 59 (T, 2), 3.77 (D, 1), 4.01 q, 1), 4.34 (dd, 1), 4, 37 (D, 1), 4.67 (D, 1), 4.76 (t, 1) , 5.03 (dd, 1) , 5 , 17th (s , 2), 7.06 (D, 2.) 7.26 (t, 1) , 7.38 (d, 2), 7 42 (S, 5), 7.44 (D, 2),

8.16 (d, 2).

Example 11a

To 4.00 g (7 mmol) of product 6b was added 40 ml of tetrahydrofuran, cooled to -78 ° C, 2.31 g (21 mmol) of sodium t-pentoxide was added and the mixture was stirred. . After 10 minutes, HPLC analysis showed some residual phenyl ester. The reaction was completed slowly. After stirring at -78 ° C for 70 minutes, the reaction mixture was poured into 100 mL of dichloromethane and 100 mL of 1N hydrochloric acid and stirred rapidly at room temperature. After 5 minutes, the organic phase was separated and washed with water (2 x 100 mL) and brine. The product solution was dried over magnesium sulfate and the dichloromethane was evaporated in a rotary evaporator. The residue was crystallized with 30 ml of ethyl acetate. After 10 minutes, this suspension was cooled in an ice bath. The enol product was filtered off and washed with cold ethyl acetate (20 mL) followed by ethyl ether. Vacuum drying at 35 ° C gave 2.05 g of product (A) which was pure by HPLC analysis. The filtrate was evaporated and the solid residue was suspended in ethyl acetate (5 mL) using an ice bath. A second crop of product (B) was obtained, which was also found to be pure by HPLC analysis. Total yield was 2.29 g, 68%.

NMR (CDCl ₃ ), δ:

1.69 (M, 1), 1.91 (M, 1), 2.41 (m, 2), 3.70 (M, 1), 4.33 (Dd, I) , 4.65 (D, 1.) , 4.77 (t, 1), 5.01 (dd, 1 5.26 (D, 1), 5.49 (D, 1), 7.44 (m, 5), 7.70 (D, 2), 8.24 (D, 2), 11, 18 (S, 1.)

Elemental analysis based on the formula C24H2] _N ₃ 0g: date: C: 60.13; H, 4.42; N, 8.76 %; found: C: 60.40; H, 4.40; N, 8.62 %. Example 11b The (5b) carboxylic acid product of formula (7b) enol

(see Comparison of Examples 10 and 11a) was combined in the following procedure. 600 g (1.206 mol) of carboxylic acid (5b) were added to 5400 ml of tetrahydrofuran at room temperature. Triethylamine (175.8 mL) and dimethylaminopyridine (9.0 g, 73.8 mmol) were added. Phenyl chloroformate (181.9 mL, 1.45 mol) in tetrahydrofuran (600 mL) was added dropwise over 20 minutes at 30 ° C. After stirring for 10 minutes, the mixture was filtered to remove the salts and then the phenyl ester solution was filtered

It was cooled to -15 ° C.

Lithium tert-butoxide (384 g, 4.8 mol) was dissolved in tetrahydrofuran (6000 mL) and cooled to -15 ° C. The dissolved base was added dropwise to the phenyl ester (~ 10 ° C) over 5-10 minutes and the resulting mixture was stirred at -10 ° C for 5 minutes. HPLC analysis indicated the reaction was complete. The reaction mixture was diluted with 660 mL of concentrated hydrochloric acid and 3,300 mL of 20% sodium chloride solution and the phases were separated. The organic phase was distilled to a slurry of 6000 g. Isopropyl alcohol (6000 mL) was added and the mixture was distilled again to a slurry (6000 g). Another 600 mL of isopropyl alcohol was added and the resulting mixture was distilled to a slurry of 9000 g. This suspension was cooled to 0 ° C, stirred for 1-2 hours, filtered and washed with 2.75 L of isopropyl alcohol and then vacuum dried at 35-40 ° C. The weight of the enol product (7b) was 512.7 g (88.7%). HPLC analysis showed 98.8% purity.

NMR (CDCl ₃ ), δ:

1.69 (m, 1), 1.90 (m, 1), 2.40 (m, 2), 3.67

(M, 1), 4.32 (dd, 1), 4.63 (d, 1) , 4.75 (t, 1) 5.00 (dd, 1), 5.24 (d, 1), 5.47 (d, 1), 7.41 (M, 5), 7.68 (d, 2), 8.22 (d, 2), 11, 17 (s, 1)

Example 12a

A phosphite / chlorine adduct was prepared at -15 ° C as described in Example 6. Triphenylphosphite (2.13 mL, 8 mmol) in CH 2 Cl 2 (2 mL) and CH 2 Cl 2 (30 mL) were added and a slight drop of chlorine was quenched with a few drops of anylene. Specifically, 1.0 g (about 8 mmol) of polyvinylpyridine polymer (PVPP), dried first in toluene azeotropes and then vacuum oven dried, was added followed by 1.92 g (4 mmol) of enol 7b. The cooling bath was removed and a room temperature bath was used. The temperature was warmed to room temperature within 3 minutes. The reaction mixture was stirred at room temperature (23-24 ° C) for 4 hours. The reaction was followed by HPLC analysis and proceeded smoothly. After 4 hours at room temperature, the polyvinylpyridine polymer was filtered off and the solution was washed with water (50 mL) and brine (2 x). The solution was dried over magnesium sulfate and evaporated to a syrup which crystallized. The crystals were slurried with 25 mL of ether for 20 minutes, then filtered and washed with ether. Vacuum drying of the white solid at 40 ° C afforded 1.75 g (88%) of the chlorinated para-nitrobenzyl ester (8b). NMR (in CDCl ₃ ) gave excellent results (trace amounts of ether). The HPLC analysis showed a purity of 94%. The major impurities were in the form of a fast moving peak corresponding to a saponified product of formula 8c (at 1.44 minutes) and an enol starting material (at 4.57 minutes). In the infrared spectrum, β-lactam was detected at 1783.9 cm1. The UV spectrum showed a peak at 271 nm, e value = 18400. The FD mass spectrum showed a strain ion at 497. Mp 206-207 ° C. Elemental analysis according to formula ^c 24 ^H 20 ^cl l ^N 3 ° 7:

Found: C, 57.90; H, 4.05; N, 8.44; Cl, 7.12;

- 45 - found: C: 57.64 , H: 4.04. N: 8, 25 Cl, 7.33 %. NMR (CDCl 3), δ: 1 80 (m, 1), 1.94 (m, 1), 2.55 (M, 2), 3.76 (M, 1), 4, 32 (dd, 1), 4.66 (d, 1) , 4.76 (T, 1), 4.96 (dd, 1 5 37 (q, 2), 7.43 (m, 5), 7.61 (D, 2), 8.22 (D, 2).

Example 12b

The phosphite / chlorine adduct was prepared by adding chlorine gas and triphenylphosphite (73.2 mL, 275 mmol) dropwise to 516 mL of dichloromethane, keeping the temperature below -15 ° C in a dry ice / acetone bath. Excess chlorine was quenched with 2 mL of anylene. Pyrimidine (21.6 mL, 275 mmol) was added followed by enol (7b) (66 g, 137.5 mmol) and ethyl acetate (516 mL). The cooling bath was removed and the reaction mixture was warmed to room temperature and stirred for 2.5 hours. HPLC analysis showed that the chlorination was complete. Water (1750 mL) was added followed by dichloromethane (500 mL) to facilitate separation of the layers. The organic layer was separated and washed with brine (2 x 1000 mL). It was dried over magnesium sulfate, filtered through a Hyflo filter and evaporated to a suspension of 290 g in a rotary evaporator. Diethyl ether (860 mL) was added slowly and the crystallization mixture was stirred for 30 min. The product was filtered, washed with diethyl ether and dried in vacuo overnight to obtain 59.9 g of the chlorinated para-nitrobenzyl ester 8b. The yield was 87.5%. HPLC analysis

Purity was 96.3%.

NMR (CDCl ₃ ), δ:

1.82 (m, 1), 1.93 (m, 1), 2.54 (m, 2), 3.74 (m, 1), <· »· ♦ <·» »♦

4.29 (Dd, 1), 4.62 (d, 1), 4.74 (t, 1), 4.94 (Dd, 1), 5.34 (q, 2), 7.40 (m, 5), 7.59 (d, 2 8.20 (D, 2).

Cleavage of the chiral auxiliary group and the non-methylcarboxy protecting group

The foregoing examples have resulted in a 3-substituted compound containing both a non-methyl, 2-carboxy protecting group and a chiral auxiliary, 7-amino protecting group.

The following examples illustrate alternative routes for the conversion of such compounds to the corresponding carbacephem. In the processes of Examples 13a to 13f, the synthesis is first performed by cleavage of the carboxy protecting group to afford the 2-carboxylic acid, which is then converted to the 7-aminocarbacephem. 16-17. In the alternative methods of Examples 1 to 4, the chiral auxiliary protecting groups are cleaved before or simultaneously with the cleavage of the carboxy protecting groups. Example 13a

To 4.98 g (10 mmol) of chlorinated para-nitrobenzyl ester 8b, 20 ml of N, N-dimethylformamide (DMF), 20 ml of methanol and 2.16 g (33 mmol) of zinc powder were added in portions. . Thereafter, 5.0 mL (77 mmol) of methanesulfonic acid was added dropwise over 30 minutes, which resulted in an exotherm to 40 ° C. We maintained this temperature with the help of a water bath. An acidic reaction of the zinc resulted in a precipitate, which however dissolved as soon as the acid residue was added to the reaction mixture. HPLC analysis after 1 h 50 min clearly showed the conversion to 2-carboxylic acid (8c). After 2 hours at 40 ° C, the mixture was filtered and the fine zinc washed with 10 mL of 1: 1 dimethylformamide / water. Dichloromethane (100 mL) and water (100 mL) were added and the mixture was stirred. The dichloromethane layer was separated and the aqueous layer was re-extracted with dichloromethane (20 mL), but only traces of product were recovered. The extracts were combined and washed with 100 ml of 10% sodium chloride solution, dried over magnesium sulfate and concentrated to 10.3 g of syrup. The syrup was diluted with 25 ml of isopropyl alcohol (iPrOH) and inoculated. The product crystallized rapidly. Isopropyl alcohol (35 mL) was added slowly, the mixture was stirred overnight at room temperature and then cooled to 0 ° C for 1 hour, but the top layer still contained some product. Hexane (25 mL) was added and HPLC analysis of the upper layer revealed less product. After adding another 25 ml of hexane and stirring at room temperature, the upper layer showed little product. Filtration and washing with isopropyl alcohol / hexane (1: 1) followed by vacuum drying at 50 ° C gave 2.63 g of a yellow solid (8c), roughly 72% yield. The NMR test was good (showed some dimethylformamide and isopropyl alcohol). HPLC analysis showed 99% purity.

NMR _(DMSO-d6) δ: 1.98 (M, 2), 2.55 (m, 2.) , 3.78 (M, 1). 4.12 (Dd, 1), 4.47 (d, 1), 4, 73 (t, 1), 5.02 (Dd,

»··« ·· »« ··· ···· · »♦ *» · »*

- 48 7.41 (m, 5), 13.5 (s, 1).

Example 13b

The cleavage of the para-nitrobenzyl ester of Example 13a was repeated with minor modifications. First, hydrochloric acid was used instead of methanesulfonic acid. To the chlorinated para-nitrobenzyl ester (4.98 g, 10 mmol) was added dimethylformamide (50 mL), cooled to 0-5 ° C, and concentrated hydrochloric acid (8.75 mL, 105 mmol) was added. The starting material crystallized upon addition of concentrated hydrochloric acid (after about 7 mL), and the mixture was warmed to room temperature and 5 mL of dimethylformamide was added. Zinc (2.29 g, 35 mmol) was added and the mixture was diluted and stirred. A cooling bath was used to maintain the room temperature (20-25 ° C) and a clear solution was obtained shortly. The residual concentrated hydrochloric acid and zinc were added. The pH was 1.00 after 20 minutes and 1.13 after 1 hour and 35 minutes. The mixture was stirred for 1 hour 45 minutes, but despite the absence of starting material, the reduced ester was slowly hydrolyzed. The mixture was filtered, washed with 5 ml of dimethylformamide on glass paper and 30 ml of water was added to accelerate the hydrolysis, which was done at an extremely rapid rate. After a reaction time of 2 hours 10 minutes, only 3% of the intermediate remained and the pH was 1.35. After 2 hours 30 minutes, the reaction was essentially complete. To the reaction mixture was added dropwise water (40 mL) and the cloudy solution was inoculated. An additional 70 mL of water was added dropwise to form a gummy solid. Methylene chloride (5 mL) was added and the mixture was stirred for 30 minutes.

The product crystallized but was not of acceptable quality - about 25% of the product was still in solution - so the mixture was extracted with dichloromethane (250 mL) followed by dichloromethane (100 mL). The methylene chloride extracts were combined and washed with 100 mL of 1N hydrochloric acid. The organic layer was extracted with saturated sodium bicarbonate solution (2 x 100 mL) and the bicarbonate extract was washed with dichloromethane (50 mL). It was then filtered through Hyflo to remove some polymer. The pH of the bicarbonate extract was adjusted to 1.5 with concentrated hydrochloric acid with the addition of a small amount of ethyl ether in order to prevent foaming due to the evolution of carbon dioxide. The product was then filtered and washed with water followed by ethyl ether. The compound of formula (8c) was dried at 50 ° C to yield 2.33 g of product (A), corresponding to 64% yield. HPLC analysis of the product showed 99.5% purity. The filtrate stood for 8 days and then the ether was evaporated. Another portion (pure by HPLC analysis) of product (B) was filtered off and dried (0.42 g, 12%). The overall yield was 76%.

Example 13c

To 54.7 g (109.9 mmol) of chlorinated para-nitrobenzyl ester 8b (1165 mL) was added ethyl acetate. Lithium iodide (21.97 g, 164.8 mmol) was added and the mixture heated at reflux (78 ° C) for 6.5 h. Heating was stopped and the mixture was stirred overnight at room temperature. 1098 ml of deionized water and 220 ml of sodium chloride solution were added and the mixture was stirred for 5 minutes. The layers were separated, the pH of the aqueous phase was slowly lowered from 6.3 to 4.0 with concentrated hydrochloric acid and inoculated with crystalline material. The pH of the product crystallized at 3.5 and 4.2. The pH was then reduced to 1.9, the mixture was stirred for 15 minutes, then filtered and washed with water (750 mL). The product was dried at 60-70 ° C. The weight of the product was 34.48 g, yield 34.8 / 39.87 = 86.5%. HPLC analysis showed 98.3% of 8c.

Example 13d

2.71 g (5 mmol) of p-nitrobenzyl-7E - [(S) -4-phenyloxazolidin-2-ηη-3-yl] -1-carba- (1-thia) -3-bromo-3- cephem-4-carboxylate was suspended in 30.5 ml of tetrahydrofuran and 4.0 g (30 mmol) of lithium iodide was added. The mixture was refluxed for about 4 hours. The resulting precipitate was filtered and washed with tetrahydrofuran (20 mL) and diethyl ether (15 mL). The material was dried. 7β - [(S) -4-Phenyloxazolidin-2-one-3-yl] -1-carba- (1-thia) -3-bromo-3-cephem-4-carboxylate in 76.2% yield we got.

Elemental analysis data were as follows:

calculated: C: 49.92. H: 3, , 42, N 6.78 0: : 19.36, Br 19.34 %; found: C: 49,39, H: 3, 41: N 6.53; 0: : 19.57, Br 19.37 %. NMR (DMSO, TFA) , δ: 1.95 (m, 2) , 2.68 (M, 2), 3.75 (M, 1), 4.10 (Dd, 1), 4, 45 (d, 1), 4.70 (T, 1), 4.98 (dd, 1)

7.35 (m, 5).

Example 13d

2.71 g (5 mmol) of p-nitrobenzyl-7 H - [(S) -4-phenyloxazolidin-2-one-3-yl] -1-carba- (1-thia) -3-bromo-3- cephem-4-carboxylate was suspended in 30.5 mL of tetrahydrofuran and 4.0 g (30 mmol) of lithium iodide was added. The mixture was refluxed for about 4 hours. The resulting precipitate was filtered and washed with tetrahydrofuran (20 mL) and diethyl ether (15 mL). The material was dried. Yield 76.2% yield 7β - [(S) -4-phenyloxazolidin-2-one-3-yl] -1-carba- (1-detia) -3-bromocephem-4-carboxylate. Elemental analysis data were as follows:

Calculated: C, 49.92; H : 3.4, N, 6.78. 0: 19,36, Br 19.34 %; found: C: 49,39, H : 3.41, N, 6.53. 0: 19.57. Br 19.37 %. NMR (DMSO, TFA) , δ: 1.95 (m, 2) , 2 , 68 (m, 2), 3.75 (M, 1), 4.10 (Dd, 1), 4, 45 (d, 1), 4.70 (t, 1). 4.98 (dd, 1

7.35 (m, 5).

Example 13e

2.95 g (5 mmol) of p-nitrobenzyl-7 H - [(S) -4-phenyloxazolidin-2-one-3-yl] -1-carba- (1-thia) -3-iodo-3- cefem-4-carboxylate was dissolved in 30.5 mL of tetrahydrofuran and 4 g (30 mmol) of lithium iodide was added. The mixture was stirred at reflux for about 7.5 hours to form a solid. After heating was stopped, ethyl acetate (30 mL) was added. The mixture was allowed to cool to room temperature and the resulting solid was filtered, washed with tetrahydrofuran: ethyl acetate (50 mL, 50 mL) followed by ethyl acetate (15 mL) followed by diethyl ether (10 mL). The solid was dried. Lithium 7S - [(S) -4-phenyloxazolidin-2-one-3-yl] -1-carba- (1-thia) -3-iodo-3-cephem in 65.6% uncorrected yield -4-carboxylate was obtained. Elemental analysis data were as follows:

calculated: C: 44.37. H, 3.07. N 6.09 J: 27.58%; found: C: 44,10, H, 3.04. N 5.80; J: 27.38%. NMR (DMSO, TFA) , δ: 1, 88 (m, 2) , 2.68 (m, 2), 3.75 (m, 1), 4.08 (Dd, 1), 4, 43 (d, 1), 4.68 (t, 1) f 4.98 (dd, 7.35 (m, 5) • Example 13f 2.0 g (15 mmol) lithium-j odid 3.06 g (5 mmol) p-

-nitrobenzyl-7S - [(S) -4-ηθηί1-οχ3ζο1ίάίη-2-οη-3-ί1] -1-carba- (1-detia) -3-trifluoromethylsulfonyloxy-3-cephem-4 carboxylate. The mixture was stirred at room temperature for about 48 hours and quenched by HPLC. Water (50 mL) was then added to the solution. The aqueous and organic layers were separated. The aqueous phase was charged to a rotary evaporator and a small amount of ethyl acetate was evaporated. A small amount of solid was then filtered off. The pH of the aqueous phase was reduced from 7.34 to about 1.89 with concentrated hydrochloric acid. At about pH 3.5, the solid began to precipitate. The mixture was stirred at pH 1.89 for about 10 minutes, then the solid was filtered and washed with water (10 mL) followed by diethyl ether (15 mL). The solid was dried. 7β - [(S) -4-Phenyloxazolidin-2-one-3-yl] -1-carba- (1-thia) -3-trifluoromethylsulfonyloxy-3-cephem in 50% yield. -4-Carboxylic acid is obtained. Elemental analysis data a

were: Calculated: C, 45.38; H, 3.17; N, 5.88; Found: C, 45.65, H, 3.31; N, 6.06%. NMR (DMSO), δ: 1.95 (m, 1), 2.03 (m, 1), 2.55 (m, 2), 3.78 (m, 4.03 (dd, 1), 4.52 (d, 1), 4.70 (t, 1), 5.02 (dd, 1), 7.40 (m, 5). Example 13g 1.67 g (12.5 mmol) lithium iodide 5.31 g (10 mmol) p- -nitrobenzil-7B - [(S) -4- phenyl-oxazolidin-2-on-3-yl ] -1-carba

(diethoxy) -3-trifluoromethyl-3-celem-4-carboxylic acid was added in 106 mL of ethyl acetate. The mixture was refluxed for about 5.6 hours. The mixture was then stirred at room temperature for 3 days. Water (100 mL) was added followed by saturated sodium chloride solution (20 mL). The layers were separated. The aqueous phase was brought to pH 4.0 by slow addition of concentrated hydrochloric acid and the mixture was inoculated. The pH was further reduced to 1.9 and the mixture was stirred for 15 minutes. The resulting solid was filtered, washed with water (50 mL) and dried in vacuo at 60 ° C. 3.20 g of 7β [(S) -4-phenyloxazolidin-2-one-3-yl] -1-carba- (1-thia) -3-trifluoromethyl-3-cephem-carboxylic acid are obtained, m.p. corresponds to a (uncorrected) yield.

Elemental Analysis a C18 ^H 15 ^N 1 ° 5 ^F 3 formula Based on: date: C: 54.55, H: 3.82; N: 7.07% F: 14.38 %; found: C: 54.78, H: : 3.97, N, 6.87. F: 14.45 %. NMR (DMSO-d6), δ: 1.67 (M, 1), 2.07 (m, 1) , 2.29 (m, 2) , 3.79 (M, 1), 4.12 (dd, 1), 4, 58 (d, 1), 4, 73 (t, 1),

5.02 (dd, 1), 7.39 (m, 5), 14.04 (bs, 1).

Example 14a

The 2-carboxylic acid (8c) prepared in Example 13a was converted to the carbacephem (9) by trimethylsilyl iodide (TMSJ) reaction. Specifically, 0.726 g (2 mmol) of acetonitrile (ACN), 1.06 mL (5 mmol) of hexamethyldisilazane and 0.72 mL (5 mmol) of trimethylsilyl iodide were added to 0.726 g (2 mmol) of the carboxylic acid 8c, and the mixture was stirred at room temperature for 4 hours. In 5 ml of acetonitrile 0.56 g (5 mmol)

1,4-Diazabicyclo [2.2.2] octane was added and the mixture was stirred at room temperature overnight. A precipitate of 1,4-diazabicyclo [2.2.2] octane hydrogen iodide was obtained. Both reactions appeared to be normal and HPLC analysis of the 1,4-diazabicyclo [2.2.2] octane reaction (removal) showed 39.1: 12.0 product: starting material with 77% conversion. To the reaction mixture was added 5 ml of 1N hydrochloric acid and the mixture was stirred at room temperature for 30 minutes. The pH was 3.55. The precipitate of 1,4-diazabicyclo [2.2.2] octane hydrogen iodide was dissolved and the desired carbacephem product 9a appeared as a precipitate. The product was filtered off and washed successively with 10 ml of 2: 1 acetonitrile / water, 5 ml of water and 5 ml of acetonitrile. After vacuum drying at 50 ° C, 0.275 g of an off-white solid was obtained. The yield was about 63.5%. The NMR spectrum (DMSO-dg, trifluoroacetic acid (TFA)) was excellent.

NMR (DMSO-d6, TFA), δ:

1.95 (m, 2), 2.67 (m, 2), 3.94 (m, 1), 4.83 (d, 1 ), 8.87 (bs, 5). Like this one Example 7 we were expecting

that the trimethylsilyl iodide reaction results in the iodoethyl intermediate containing the opened oxazolidinone ring. The hydrodehyde remover and 1,4-diazabicyclo [2.2.2] octane trapping agent give the enamine and the hydrolysis converts this product to the desired carbacephem 9a.

Example 14b

The trimethylsilyl iodide reaction of Example 14a was substantially repeated, but not in acetonitrile but in dichloromethane. To 0.363 g (1 mmol) of carboxylic acid (8c) was added dichloromethane (10 mL). Hexamethyldisilazane (0.43 mL, 2 mmol) and trimethylsilyl iodide (0.36 mL, 2.5 mmol) were then added. The mixture was stirred for 1 hour and then additional 0.1 ml (0.5 mmol) of hexamethyldisilazane was added. The resulting solution was stirred at room temperature overnight, then additional 0.11 mL (0.5 mmol) of hexamethyldisilazane and 0.07 mL (1.5 mmol) of trimethylsilyl iodide were added and stirred for 1 hour. The trimethylsilyl iodide reaction showed a slight HPLC peak after 4.8 minutes, probably because the trimethylsilyl iodide present was in excess of hexamethyl56.

-disilazane. Otherwise, 13% of the starting material and 73% of the iodoethyl intermediate were clearly detected. At 0 ° C, 0.34 g (3 mmol) of 1,4-diazabicyclo [2.2.2] octane was added. The ice bath was removed and the temperature rose to room temperature. The addition of 1,4-diazabicyclo [2.2.2] octane immediately precipitated and slowly precipitated the enamine. After 4 hours 40 minutes, an additional 1 equivalent of 1,4-diazabicyclo [2.2.2] octane was added and the solution was stirred overnight. The reaction appeared to stop at about 18: 9 product: starting material. An additional 0.5 mL of trimethylsilyl iodide (about 3.5 mmol) was added, resulting in significant starting material conversion to the iodoethyl intermediate. An additional 0.29 mL of trimethylsilyl iodide (about 2 mmol) was added to the reaction mixture and stirred overnight. After 3.59 minutes, HPLC analysis revealed a large number of iodoethyl intermediates and no change in the enamine product. The amount of starting material was only 6%. Addition of 0.62 g (5.5 mmol) of 1,4-diazabicyclo [2.2.2] octane in this reaction to 8.5 equivalents of trimethylsilyl iodide and 9.5 equivalents of 1,4-diazabicyclo [2.2.2]. 2] octane. The precipitation started again and after 3 days at room temperature HPLC analysis showed 30%: 10%, i.e. 3: 1 product: starting material. The color of the reaction mixture was light. Addition of 5 ml of water resulted in complete dissolution of the precipitate within 3 minutes. The pH was 4.8 and was reduced to 2.0 by adding concentrated hydrochloric acid for 5 minutes. The pH was then raised to 3.9 with triethylamine, and no precipitate appeared. Addition of 5 ml of acetonitrile increased the pH to 4.0 and addition of additional acetonitrile resulted in some precipitation. The product was filtered from the biphasic mixture, washed with a mixture of water (4 mL) and acetonitrile (10 mL), and then ethyl ether, dried under vacuum at 40 ° C for 2 hours to give 0.115 g of an off-white solid. HPLC analysis showed a purity of 98.6% with a 53% yield of carbacemfem 9a. Elemental analysis based on the formula CgH ^ Cl ^^ O ^:

Found: C, 44.36; H, 4.19; N, 12.93; Cl, 16.37;

Found: C, 42.62; H, 4.15; N, 11.95; Cl, 16.88.

NMR (DMSO-d _5, TFA) δ:

1.97 (m, 2), 2.69 (m, 2), 3.94 (m, 1), 4.86 (d, 1),

8.91 (bs, 5).

Example 14c

2-Carboxylic acid 8c (30.0 g, 82.7 mmol) was added to 415 mL of acetonitrile at room temperature. Hexamethyldisilazane (43.72 mL, 207 mmol, 2.5 equiv.) Followed by trimethylsilyl iodide (29.81 mL, 207 mmol, 2.5 equiv.). The mixture was stirred for 6 hours at room temperature. HPLC analysis showed that the reaction was complete. The reaction mixture was cooled to 0-5 ° C and 27.8 g (248.1 mmol, 3.0 eq.) Of 1,4-diazabicyclo [2.2.2] octane (with slight heat evolution) were added. The mixture was stirred at 0-10 ° C overnight. HPLC analysis showed that the reaction was complete.

After the reaction was completed, 248 mL of 1N hydrochloric acid was added (the temperature increased from 8 ° C to 24 ° C during hydrolysis). The product precipitated rapidly at a pH of 4.1. The pH was lowered to 3.7 with a sufficient amount of concentrated hydrochloric acid (4.0 mL of hydrochloric acid was required) and the mixture was stirred at room temperature for 30 minutes. It was filtered and washed with 250 ml of 2: 1 acetonitrile / water, 350 ml of acetonitrile and dried in vacuo at 60 ° C. Yield: 12.44 g (69.6%). HPLC analysis showed 91.8% purity of product 9a.

Example 15a

In another alternative procedure, 0.363 g (1 mmol) of carboxylic acid 8c was treated with 3.8 mL of acetonitrile at 0 ° C followed by 0.32 mL (2 mmol) of allyl trimethylsilane. A drop of trimethylsilyl iodide was added and after 70 minutes, another drop was added and the mixture was stirred. The allyl trimethylsilane silylated the acid group of the starting material (8c) under the catalytic action of hydrogen iodide from the trimethylsilyl iodide reaction. The suspension was clear and significantly diluted after the first drop with trimethylsilyl iodide, then completely clear by the second drop and further stirring at room temperature for 1 hour. HPLC analysis showed no decomposition. A complete equivalent of trimethylsilyl iodide (0.14 mL, 1 mmol) was added and after 1 hour the HPLC showed a clear reaction to the open ring intermediate. Allyl trimethylsilane has been found to be a good scavenger. The mixture was stirred at room temperature overnight but the opening of oxalidinone was very slow after the first hour. Another equivalent amount of trimethylsilyl59

iodide was added. After 2 hours, HPLC analysis showed the starting to intermediate ratio to be 13.6: 66.3, 83% complete. After 3 hours, the conversion was 86%. At this time, 2 equivalents of 1,4-diazabicyclo [2.2.2] octane (0.22 g, 2 mmol) was added and the mixture was stirred for 4 days. HPLC analysis showed that there was a lot of conversion to the starting oxazolidinone. The product: starting material ratio was 34: 23.4, i.e. the reaction was 59% complete. Water (1.6 mL) was added and stirred at pH 4.0 for 30 min. The mixture was filtered and washed with 6 mL of 2: 1 acetonitrile / water. Drying gave 0.095 g of 9a, 44% yield.

Example 15b

The above procedure for trimethylsilyl iodide, hexamethyldisilazane was repeated except for 2-carboxylic acid substituted with 3-trifluoromethyl. To the jacketed flask was added 15 mL of acetonitrile and 2.63 mL (12.5 mmol) of hexamethyldisilazane and 1.80 mL (12.5 mmol) of trimethylsilyl iodide were added. The solution turned pale yellow. 3-Trifluoromethyl-2-carboxylic acid (1.98 g, 5 mmol) was added and the flask was rinsed with the remaining 10 mL of acetonitrile. The solid dissolved in 1-2 minutes and the solution was then stirred at room temperature for 6 hours. The coolant at -3 ° C was introduced into the jacket of the flask to cool the flask to 0 ° C, and after about 20 minutes, 1.68 g (15 mmol) of 1,4-diazabicyclo [2.2.2] octane was added. . A precipitate formed immediately. The mixture was stirred cold overnight.

HPLC analysis indicated that product was present. After cooling was stopped, 1N hydrochloric acid (15 mL) was added and the temperature rose to 17 ° C. The pH was adjusted with concentrated hydrochloric acid from 4.34 to 3.66. The mixture was stirred for 30 minutes and the slowly formed precipitate was filtered off. The precipitate was washed with 15 mL of 2: 1 acetonitrile: water followed by 20 mL of acetonitrile to give a white powder (3-trifluoromethylcarbacephem) which was dried in a vacuum oven to 0.77 g. This corresponds to a yield of 61.6%. NMR showed small amounts of water and starting material in the product.

NMR _(DMSO-d6, TFA): delta

1.76 (m, 1), 2.03 (m, 1), 2.37 (m, 2), 3.94 (m, 1), 4.84 (d, 1), 8.83 (bs) , 5).

Example 15c

The procedure of Example 15b was repeated, using 3-iodocarboxylic acid. Hexamethyldisilazane (1.06 mL, 5 mmol) and trimethylsilyl iodide (0.71 mL, 5 mmol) in a solution of 3-iodine (0.91 g, 2 mmol) in acetonitrile (10 mL), azeotropic distillation of acetonitrile (20 mL) dried. After 4 hours, the reaction seemed to be progressing well and a precipitate had formed.

After 5.5 hours, the intermediate peak was 75%. The solution was cooled to 5 ° C and 0.67 g (6 mmol) of 1,4-diazabicyclo [2.2.2] octane was added. The consistency and color of the precipitate changed slightly. The mixture was stirred at 3 ° C overnight.

HPLC analysis revealed 22% product and 33% starting material. The intermediate was converted to the starting material, probably because water reacted. After removal of the cooling bath, 6 mL of 1N hydrochloric acid was added to dissolve some of the precipitate (starting material). The mixture was then filtered and washed with 5 mL of acetonitrile. The solid still contained some starting material and was suspended in 5 ml of acetonitrile. The filtrate did not contain any product. The product was re-filtered and washed with 5 mL of acetonitrile, still containing 3.7% starting material. After drying in the oven 0.20

g of 3 iodocarbacephem we got, which corresponds to a yield of 32.7% NMR _(DMSO-d6, TFA); δ: 1.85 (bs, 2), 2.77 (m, 2), 3.93 (m, 1), 4.80 (d, 1) 8.89 (bs, s). Example 15d

The procedure of Example 15b was repeated with 0.813 g (2 mmol) of 3-bromocarboxylic acid, 10 mL of acetonitrile, 1.06 mL (5 mmol) of hexamethyldisilazane and 0.71 mL (5 mmol) of trimethylsilyl iodide. The reaction mixture was stirred overnight, cooled to 0 ° C, and 0.67 g (6 mmol) of 1,4-diazabicyclo [2.2.2] octane was added, resulting in a pale yellow precipitate. This mixture was stirred overnight at 0 ° C and the cooling bath was removed. To the mixture was then added 6 ml of 1N hydrochloric acid and the pH was adjusted from 4.51 to 3.71 with concentrated hydrochloric acid. The product appeared as a precipitate. After stirring for 0.5 h, the mixture was filtered and washed with 10 mL of 2: 1 acetonitrile: water and then 10 mL of acetonitrile. The white, slightly adherent product in a vacuum oven »« »« * »a * ί • * 9 · · ··· · ·

It was dried at 50 ° C to give 0.18 g (34.4%) (uncorrected). HPLC analysis indicated that about 3% of starting material remained in the product. NMR of the product showed good results, indicating some starting material and ammonium salt.

NMR (DMSO-d6, TFA), δ:

1.94 (m, 2), 2.74 (m, 2), 3.93 (m, 1), 4.81 (d, 1),

8.88 (bs, 5).

Example 15e

The trimethylsilyl iodide reaction was repeated with 3-triflate (OSO2CF3) carboxylic acid. The triflate starting material (0.95 g, 2 mmol) was dissolved in acetonitrile (30 mL) and 2 mL of acetonitrile was distilled off to dry the starting material. The solution was cooled to room temperature and 1.06 mL (5 mmol) of hexamethyldisilazane and 0.71 mL (5 mmol) of trimethylsilyl iodide were added. Precipitation did not appear at first, but after a few hours precipitation began to appear. After 6 hours, a small amount of starting material was still present. The solution was then cooled to 0-3 ° C in a cooling bath and 0.56 g (5 mmol) of 1,4-diazabicyclo [2.2.2] octane was added, resulting in a precipitate. The mixture was stirred overnight and the temperature was allowed to rise to room temperature. 6 mL of 1N hydrochloric acid was added and the entire precipitate dissolved. The pH was adjusted from 2.38 to 3.7 with 10% sodium bicarbonate solution. A solid precipitates out of solution. The mixture was stirred for 0.5 h, then filtered and washed with 9 mL of water: acetonitrile 1: 2 followed by 5 mL of acetonitrile to give a white solid. HPLC analysis revealed a 3% triflate carbacephem nucleus which was dried in an oven to 0.14 g, which corresponds to a% yield. The filtrate contained only about 3% product.

NMR (DMSO-d6, TFA), δ:

1.97 (m, 1), 2.07 (m, 1), 2.64 (m, 2), 3.97 (m, 1),

4.86 (d, 1), 8.82 (bs, 5).

Example 15f

The trimethylsilyl reaction was carried out with 2-carboxylic acid substituted with 3-trifluoromethyl. To 470 g (1.187 mol) of 3-trifluoromethyl compound was added 5.94 L of acetonitrile at room temperature and treated with hexamethyldisilazane (627 mL, 2.967 mol) followed by trimethylsilyl iodide (427 mL, 2.967 mol). After stirring at room temperature for 6 hours, HPLC analysis indicated that the reaction was complete. After cooling to 0-5 ° C, 1,4-diazabicyclo [2.2.2] octane (399 g, 3.56 mol) was added. This mixture was stirred at 0-10 ° C overnight. HPLC analysis indicated that the removal reaction was complete. 3.56 L of 1N hydrochloric acid was added, causing a heat build up (temperature rose to 26 ° C). The hydrolysis product precipitated rapidly. The pH was adjusted from 4.25 to 3.7 with 60 ml of concentrated hydrochloric acid. After stirring for 30 minutes at room temperature, the product was filtered off and washed with 3.56 L of 2: 1 acetonitrile: water followed by 4.75 L of acetonitrile. It was dried under vacuum at 60 ° C overnight to 250.7 g of 3-trifluoromethylcarbacephem, which corresponds to a yield of 84.4%. A HPLC ··· · ♦ · »·· · ν« «·· ♦ · • · ♦» · «• t · · * · 4«

- 64 analyzes showed a product purity of 92.5% with a known contaminant content of 5.5% from the starting material.

NMR (DMSO-d6, TFA), δ:

1.75 (m, 1), 2.03 (m, 1), 2.38 (m, 2), 3.97 (m, 1), 4.88 (d, 1), 8.85 (bs) , 5).

Example 16

As an alternative to the procedures of the Examples 13a-15e above, the chiral auxiliary side chain may be carried out before or simultaneously with the removal of the non-methyl carboxy protecting group, as shown below. This synthesis route is described in Table IV. outline the reaction scheme.

To 0.50 g (1 mmol) of chlorinated para-nitrobenzyl ester 8b was added 10 mL of dichloromethane at room temperature. Trimethylsilyl iodide (0.29 mL, 2 mmol) and hexamethyldisilazane (0.43 mL, 2 mmol) were added and the mixture was stirred at room temperature for 1 hour. After about 40 minutes, about 19% of the starting material was converted to the opened cyclic intermediate iodide. The mixture was then refluxed to give 34% intermediate after 10 minutes, 40% after 30 minutes, 43% after 45 minutes, and 45% after 1 hour 45 minutes. After refluxing the reaction mixture for 6 hours, the iodoethyl intermediate content was 46.6%. The reaction mixture was allowed to stand at room temperature for 16 hours, after which time a slight ammonium iodide coating was formed on the condenser. An additional 1 equivalent (0.21 mL, 1 mmol) of hexamethyldisilazane was converted to the starting material. ·· ···· · «. · ··

- 65 rebounds were observed, leaving only 18% of the intermediate. The addition of 1 equivalent (0.14 mL, 1 mmol) of trimethylsilyl iodide changed the hydrolysis conditions and HPLC showed a clear 46% intermediate. This increased to 61% in about 55 minutes. After the addition of 0.5 equivalents of hexamethylsilyl iodide, 28% of the starting material and 46% of the intermediate were weighed, as a result of which the hydrolysis conditions became basic. The ratio of the intermediate increased with 0.5 ml of methanol and 1 drop of phosphoric acid. With the addition of additional 0.5 equivalents of trimethylsilyl iodide, the reaction initially seemed to proceed but was then stopped at 10% starting material. An additional 0.25 equivalent of trimethylsilyl iodide reduced the starting material content to 7.7% over 5 minutes. After 35 minutes, things didn't change much. The reaction mixture was cooled to -10 ° C and 4.25 mmol of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) was added dropwise via syringe. The resulting heat build up raised the temperature of the reaction mixture to 0 ° C and HPLC analysis showed a recovery of the starting material, which simply means that removal was not yet complete and the hydrolysis conditions were basic. After 30 minutes at 0 ° C, the removal was greatly advanced, after 2.10 minutes the desired 7-amino product 8d and acetophenone were obtained after 1.58 minutes by hydrolysis of the formed enamine and silyl carbamate.

hours after 25 minutes, about two-thirds of the reaction ν · ··· «· 4 <· · · · · · · · · · · · · · · · · · · ·

- 66 passed. After standing at 0 ° C for many hours, the mixture was placed in a refrigerator at -16 ° C. HPLC analysis showed good reaction with only 8% starting material. After 1.13 minutes, the peak increased slowly, indicating the presence of saponified carbacephem nucleus. Concentrated hydrochloric acid (0.33 mL) was added directly to the methylene chloride reaction solution while stirring at 0 ° C. The ice bath was removed and the temperature was allowed to rise to room temperature. The resulting precipitate was filtered off, washed with dichloromethane and dried to give a buttery solid (0.24 g). HPLC analysis revealed the hydrochloride (8d) (barely iodide) and many carbacephem nuclei (9a) resulting from ester cleavage. Ethyl acetate (20 mL) was added to the filtrate to give an oily solid. The solvent (mainly acetophenone) was decanted, solids (B) were dissolved in dichloromethane and 0.1 mL concentrated hydrochloric acid was added. Some precipitate formed, but the mixture was gummy. The mixture was evaporated and the resulting mixture was stirred in dichloromethane (25 mL). Filtration gave an orange / red solid (C). NMR (DMSO) showed good results for product (C), carbacephem (9a), and a large -NH 2 ^{+ +} signal.

Example 17

The trimethylsilyl iodide reaction of Example 16 cleaved the chiral auxiliary side of the amine and also cleaved a portion of the para-nitrobenzyl ester, resulting in a product having, in part, the carbacephem nucleus of formula 9a and partially has an ester with a nucleus. This mixture was subjected to the following ester cleavage reaction.

To 0.22 g of the product of Example 16, 5 ml of dimethylformamide and 1 ml of water were added and the mixture was placed in an ice bath. Concentrated hydrochloric acid (0.5 mL) and zinc powder (0.13 g, 2 mmol) were added and the ice bath was removed. The temperature rose to 15 ° C within 30 minutes. At this point, HPLC analysis indicated that the ester removal was complete. The mixture was filtered through glass tissue paper to remove fine particulate zinc, which was then washed with 1 mL of dimethylformamide. The pH of the solution was adjusted from 1.2 to 4.5 with triethylamine. The solution was clear for less than one minute, and then the product began to crystallize. The mixture was cooled in an ice bath, washed with 1 ml of dimethylformamide and then with acetonitrile. The light cream product was dried in vacuo to give 0.027 g of 9a. HPLC analysis showed excellent results, 99% purity. The HPLC of the filtrate indicated a small amount of product. The yield of starting para-nitrobenzyl ester 8b of Example 16 was about 12.5%. 5 mg of the product was dissolved in diethyl sulfoxide with the addition of 1 drop of trifluoroacetic acid and the result of the NMR analysis corresponded to the desired carbacephem product 9a. NMR, dimethylformamide, ammonium chloride, triethylamine and possibly C-7 epimer showed traces (approximately 5% estimated). The UV peak at λ = 2740 at 264 nm. The melting point (with decomposition) was 203 ° C.

Elemental analysis data were as follows:

calcd: C: 44, , 35, H, 4.19; N, 12.93. Cl: 16.37 %; found: C: 43, , 70, H, 4.55; N, 13.16. Cl: 15.89 %. NMR (DMSO-d6, TFA), , δ: 1.19 (m, 1), 2.00 (m, 1), 2.69 (m, 2), 3.94 (m, 1 4.84 (d, 1), 8.92 (bs, 5).

Although the invention has been described in detail above, this description is intended to be illustrative and not limiting. It is to be understood that only the preferred embodiments and embodiments have been described and that all changes and modifications which are in the spirit of the invention are intended to be protected.

Claims (2)

PATENT CLAIMS CLAIMS 1. Compounds of formula (I) wherein: R-L is 2-furyl, naphthyl, carboxy, amido or halogen; R ₂ is a carboxy protecting group or hydrogen; and R ₃ is phenyl, C 1 -C 4 alkylphenyl, halogenated phenyl, C 1 -C 4 alkoxyphenyl, naphthyl, thienyl, furyl, benzothinyl or benzofuryl. Second 1. . A compound according to claim 1, wherein characterized in that ^r 2 meaning methyl or p-nitrobenzyl. 3. THE 2 . A compound according to claim 1, wherein well analyzed, that rl meaning 2-furanyl. 4th THE 3. A compound according to claim 1, wherein well analyzed, that ^R 3 meaning phenyl. The compound of claim 1, wherein the compound is [3 (4S), 3S, 4R] -3- [4-phenyloxazolidinon-3-yl] -4- [2-furanyl-vinyl] -2 azetidinone-1-acetic acid methyl ester. 6. Compounds of formula (Ia), characterized in that: R-L is 2-furyl, naphthyl, phenyl, 1,2 or 3, Phenyl substituted with C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, nitro, carboxy or amido or halogen, or COOR ₄ or COSR ₄ - wherein OR 4 and SR 4 are leaving groups, and R 4 is C 1-6 alkyl, C 2-6 alkenyl, phenyl or 1,2 or 3, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, nitro, a carboxylic acid derivative containing a leaving group substituted by a carboxy, amido or halogen atom; R ₂ is a carboxy protecting group or hydrogen; and R ₃ is phenyl, C 1-4 alkylphenyl, halogenated phenyl, C 1-4 alkoxyphenyl, naphthyl, thienyl, furyl, benzothienyl or benzofuryl. The compound of claim 6, wherein R ₂ is methyl or p-nitrophenyl. The compound of claim 7, wherein R 4 is 2-furyl. The compound of claim 8, wherein [3 (4S), 3S, 4R] -3- [4-phenyl-2-oxazolidinon-3-yl] -4- [2-furanylethyl] - 2-azetidinone-1-acetic acid methyl ester. 10. The compound of claim 8, wherein: [3 (4S), 3S, 4R] -3- [4-phenyl-2-oxazolidinon-3-yl] -4- [furanylethyl] -2- azetidinone-l-acetic acid (4-nitrophenyl) methyl ester. 11. The compound of claim 8, wherein [3 (4S), 3S, 4R] -3- [phenyl-2-oxazolidinon-3-yl] -4- [2-furanylethyl] -2- azetidinone-1-acetic acid. 12. The compound of claim 7, wherein R-L is a carboxyl group. 13. The compound of claim 12, wherein R3 is phenyl. 14. The compound of claim 13, wherein [3 (4S), 3S, 4R] -3- [4-phenyl-2-oxazolidinon-3-yl] -1- [2-methoxy-2-oxoethyl ] -2-azetidinone-4-propanoic acid. 15. The compound of claim 13 wherein [3 (4S), 3S, 4R] -3- [4-phenyl-2-oxazolidinon-3-yl] -1- [2- [4-nitro- phenyl) methoxy] -2-oxoethyl] -2-azetidinone-4-propanoic acid. 16. The compound of claim 7, wherein R1 is phenylcarboxyl. 17d. A compound according to claim 16 wherein R3 is phenyl. 18. The compound of claim 17, wherein [3 (4S), 3S, 4R] -3- [4-phenyl-2-oxazolidinon-3-yl] -1- [2-methoxy] -2- oxoethyl] -2-azetidinone-4-propanoic acid phenyl ester. 19. The compound of claim 17, wherein: [3 (4S), 3S, 4R] -3- [4-phenyl-2-oxazolidinon-3-yl] -1- [2 - [(4-nitrophenyl) ) -methoxy] -2-oxoethyl] -2-azetidinone-4-propanoic acid phenyl ester. 20. A compound of formula (Ib): wherein R ₂ is a carboxy protecting group or hydrogen, R3 is phenyl, C1 -C4 alkylphenyl, halogenated phenyl, C1 -C4 alkoxyphenyl, naphthyl, thienyl, furyl, benzothienyl or benzo72 furyl; and X is hydroxy, C 1-6 alkyl, C 1-6 substituted alkyl, C 1-4 alkoxy, C 1-4 alkylthio, trifluoromethyl, C 2-6 alkenyl, 2- C 6 -C 6 substituted alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 substituted alkynyl, phenyl, substituted phenyl, C 1 -C 6 alkyloxymethyl, phenyl-C 1 -C 6 alkyloxymethyl- , tri (C 1-6) alkylsilyloxymethyl, trifluoromethylsulfonyloxy, nitrile or phenoxy or halogen. 21. A compound according to claim 20, characterized in that R ₂ represents a methyl or p-nitrophenyl group. 22. A compound according to claim 21 wherein X is hydroxy. 23. The compound of claim 22, wherein [7 (4S), 7S, 6R] -7- [4-phenyl-2-oxazolidinon-3-yl] -3-hydroxy-8-oxy-1 azabicyclo [4.2.0] oct-2-ene-3-carboxylic acid methyl ester. 24. The compound of claim 22, wherein [7 (4S), 7S, 6R] -7- [4-phenyl-2-oxazolidinon-3-yl] -3-hydroxy -8-oxo-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (4-nitrophenyl) methyl ester. 25. A compound according to claim 21 wherein X is chlorine. 26. The compound of claim 25, wherein: [7 (4S), 7S, 6R] -7- [4-Phenyl-2-oxazolidinon-3-yl] -3-chloro-8-oxo-1- azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid methyl ester. here 27. The sesintine compound of claim 25, wherein [7 (4S), 7S, 6R] -7- [4-phenyl-2-phenyl-2-oxazolidinon-3-yl] chloro-8-oxo l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (4-nitrophenyl) - methyl ester. 28. The compound of claim 20, wherein R2 is hydrogen and X is chlorine. 29. The compound of claim 28, wherein: [7 (4S), 7S, 6R] -7- [4-Phenyl-2-oxazolidinon-3-yl] -3-chloro-8-oxo-1 azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. 30. A process for preparing a compound of formula (V): wherein X is halogen, C 1-6 alkyl, C 1-6 substituted alkyl, C 1-4 alkoxy, C 1-4 alkylthio, trifluoromethyl, C 2-6 alkenyl, C 2-6 substituted alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 substituted alkynyl, phenyl, substituted phenyl, C 1 -C 6 alkyloxymethyl, phenyl (C 1 -C 6) alkyloxymethyl, tri (1-6 carbon atoms). (C 1 -C 4) alkylsilyloxymethyl, trifluoromethylsulfonyloxy, nitrile or phenoxy, characterized in that a compound of formula (IV) wherein R2 is a carboxy protecting group or a hydrogen atom, R 3 is phenyl, C 1-4 alkylphenyl, halogenated phenyl, C 1-4 alkoxyphenyl, naphthyl, thienyl, furyl, benzothienyl or benzofuryl, and X has the meaning given above • · compound with trimethylsilyl iodide. 31. A A process according to claim 30, characterized in that such (IV) reacting a compound of the formula: wherein: X is chlorine. 32. A A process according to claim 30, characterized in that such (IV) reacting a compound of the formula: wherein: R ₂ is hydrogen. 33. A The method of claim 32, wherein: such (IV) reacting a compound of the formula: wherein: X is chlorine. 34. A A process according to claim 30, characterized in that such (IV) reacting a compound of the formula: wherein: R ₂ is methyl. 35. A The process of claim 34, wherein such (IV) reacting a compound of the formula: wherein: X is chlorine. 36. A A process according to claim 30, characterized in that the compound of formula IV wherein R ₂ is hydrogen is prepared in a preceding step by reacting a compound of formula V wherein R ₅ is a carboxy protecting group and R 3 and X are as defined above; compound saponified. 37. A The process of claim 36, wherein such (IV) reacting a compound of the formula wherein a the carboxy protecting group is methyl. 38. The method of claim 36, wherein such (IV) reacting a compound of the formula: wherein: the carboxy protecting group is a p-nitrobenzyl group. 39. A The method of claim 38, wherein: such (IV) reacting a compound of the formula: wherein: X is chlorine. 40. A The method of claim 39, wherein such (IV) reacting a compound of the formula: wherein: R3 is phenyl. 41. A A process according to claim 30, characterized in that such (IV) reacting a compound of the formula: wherein: R ₂ is a carboxy protecting group and is in the first step, converting the chiral auxiliary with trimethylsilyl iodide to an intermediate of formula (VI) wherein R2 and X are as defined above over, then saponifying the intermediate compound. 42. A The method of claim 41, wherein such (IV) reacting a compound of the formula: wherein: the carboxy protecting group R _{2 is} not methyl. 43. A The method of claim 42, wherein: such (IV) reacting a compound of the formula: wherein: the carboxy protecting group R _{2 is a} p-nitrobenzyl group. 44. A The process of claim 43, wherein such (IV) reacting a compound of the formula: wherein: X is chlorine. 45. A The method of claim 44, wherein: such (IV) reacting a compound of the formula: In formula 76, R3 is phenyl. 46. A process according to claim 30 wherein X is halogen, C 1-6 alkyl, C 1-6 substituted alkyl, C 1-4 alkoxy, C 1 -C 4 alkylthio, trifluoromethyl, C 2 -C 6 alkenyl, C 2 -C 6 substituted alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 substituted alkynyl, phenyl, substituted phenyl -, C 1-6 alkyloxymethyl, phenyl (C 1-6) - -alkyloxymethyl, tri (C 1 -C 6) alkylsilyloxymethyl, nitrile, phenoxy, chloro, bromo, iodo or trifluoromethyl or trifluoromethylsulfonyloxy, and As a preliminary step, the first reagent is prepared by replacing a compound of formula VII wherein R ₂ and R 3 are as defined above with a hydroxy group. 47. The process of claim 46, further comprising the step of preparing a reagent of formula IV by reacting a compound of formula 6 wherein L is OR 4 or SR ₄ , and R 4. is C 1-6 alkyl, C 2-6 alkenyl, phenyl or substituted with 1, 2 or 3 substituents such as C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, nitro, phenyl substituted with carboxy, amido or halogen; R ₂ is a carboxy protecting group; and R3 is phenyl, C1 -C4 alkylphenyl, halogenated phenyl, C1 -C4 alkoxyphenyl, naphthyl, thienyl, furyl,